Notch信号通路在T-ALL细胞中的作用及其机制研究
|
摘要
第一部分
siRNA介导的Notchl下调对T-ALL细胞增殖凋亡影响
研究背景:
T细胞急性淋巴细胞白血病(T-ALL)是一类严重威胁人类健康的血液系统恶性疾患,在儿童及成人发病率较高。目前主要采取联合化疗来治疗白血病,但患者长期生存率仍较低,尤其是在成人T-ALL亟需完善治疗措施以改善预后。白血病的发生是由于癌基因的激活,抑癌基因的失活,导致细胞异常增殖、分化障碍和凋亡受阻。涉及T-ALL发病的分子机制非常复杂。
Notch信号与肿瘤的关系最早发现于急性T淋巴细胞白血病,t(7;9)(q34;q34.3)染色体易位使9号染色体上Notch 1基因的胞内段编码区与7号染色体上T细胞受体(T cell receptor,TCR)β基因的增强子和启动子区融合,导致Notch信号组成型激活,引起了肿瘤的发生。最近有学者报道,约50%T-ALL病人存在Notchl激活的突变,说明Notchl的异常激活是T-ALL的重要发病机制。γ分泌酶抑制剂(gamma secretase inhibitor,GSI)能够有效抑制Notchl的激活,但近期多数研究报道GSI只对人或鼠的一小部分细胞株起作用。此外,GSI作用不专一,可以阻断所有Notch受体并影响其他涉及增殖的蛋白。因此,我们利用RNA干扰技术特异性下调Notch表达深入探讨Notchl在T-ALL的作用及机制。
研究目的:
研究Notchl信号对T-ALL细胞增殖、凋亡和周期等生物学行为的影响,以揭示T-ALL发病机制并为白血病的靶向治疗开辟新的途径。
研究方法:
1.体外培养T-ALL细胞系SupT1,Jurkat。Yrizo1方法提取组织总RNA,在一定的反应体系中逆转录成cDNA,PCR方法检测Notchl,HES-1在mRNA水平的表达情况。
2.免疫细胞化学染色:体外培养T-ALL细胞系SupT1和Jurkat,细胞固定后用Notch1抗体对标本进行免疫染色,以检测Notch1在T-ALL细胞中的表达情况。
3.siRNA片段的转染:取指数生长期细胞消化计数后按8.16×10~5/ml接种于24孔细胞培养板中,后应用Lipofectamine2000将针对Notch1的siRNA片段转染T-ALL细胞SupT1和Jurkat。72小时后real-time PCR方法检测siRNA片段对Notch1 mRNA表达的阻断效率。
4.MTT方法检测siRNA片段对T-ALL细胞增殖的影响:取指数生长期细胞消化计数后按5×10~3个/孔接种于96孔细胞培养板中,后转染siRNA片段。转染后24、48、72小时MTT方法检测小干扰片段对细胞增殖的影响。
5.流式细胞术检测siRNA片段对细胞周期的影响:取指数生长期细胞接种于细胞培养板中,后转染siRNA片段,转染后72小时收集细胞,PI染色后利用流式细胞仪检测细胞周期的变化。
6.流式细胞术检测siRNA片段对细胞凋亡率的影响:取指数生长期细胞接种于细胞培养板中,转染siRNA片段,转染后72小时收集细胞,AnnexinV/PI双染后利用流式细胞仪检测细胞凋亡率的变化。
7.MTT方法检测siRNA片段对T-ALL细胞化疗药物敏感性的影响:取指数生长期细胞接种于细胞培养板中,24小时后转染siRNA片段。转染后24小时加入不同浓度的化疗药物阿霉素孵育48小时,MTT检测细胞增殖情况。
8.Western blot检测通路相关蛋白表达情况:取指数生长期细胞接种于10cm培养皿,24小时后转染siRNA片段,转染后72小时收集细胞,提取细胞总蛋白,Western blot检测通路相关蛋白的表达情况。
研究结果:
1.PCR结果显示Notch1和HES-1均在T-ALL细胞系SupT1和Jurkat中表达。
2.免疫细胞化学染色方法结果显示两种细胞均存在Notch1蛋白的表达且存在不同定位。
3.针对Notch1的siRNA片段可以有效下调Notch1的表达:siRNA转染后72小时,SupT1和Jurkat细胞干扰组Notch1 mRNA的表达较对照组分别下降91.8%±4.56%和90.2%±7.84%(P＜0.05)。SupT1和Jurkat细胞干扰组Notch1蛋白亦出现明显的下调。
4.MTT检测发现在48、72及96 h,siRNA介导的Notch1的下调明显的抑制SupT1细胞的增殖(P＜0.05),而Jurkat细胞的增殖没有受到明显的影响(P＞0.05)。
5.SupT1转染siRNA后72小时,流式细胞仪检测细胞周期分布,干扰组为:G_0/G_1:62.85%,而对照组细胞的周期分布为:G_0/G_1:46.17%,与对照组比较G_0/G_1细胞增多,下调Notchl的表达能够导致SupT1的细胞周期阻滞于G_0/G_1期,而对Jurkat细胞的周期无明显作用。
6.SupT1细胞转染siRNA后72小时,AnnexinV/PI双染后流式细胞仪检测细胞凋亡率,干扰组早期、晚期凋亡率分别为9.01%、12.41%,对照组凋亡率为4.13%、4.84%;Jurkat转染siRNA后72小时,干扰组凋亡率与对照组无明显改变。下调Notch1的表达能够显著增加SupT1细胞的凋亡率。
7.SupT1和Jurkat细胞转染后24小时,加入阿霉素作用48小时。结果显示SupT1细胞干扰组与对照组阿霉素的IC50值分别为0.05μg/ml和0.21μg/ml(P＜0.05)。SupT1细胞干扰组与对照组相比阿霉素诱导的凋亡率增加了2.4倍。Jurkat细胞干扰组与对照组相比无明显差异(P＞0.05)。
8.SupT1细胞干扰组cyclin D1及CDK2蛋白出现明显的下调,p21蛋白的表达则明显增高。Jurkat细胞干扰组cyclin D1及CDK2蛋白未出现明显的改变,p21蛋白的表达略增高。SupT1细胞干扰组p-Akt蛋白明显降低,而Jurkat细胞干扰组与对照组相比无明显改变。
结论:
1.siRNA可以有效阻断Notch1的表达。
2.siRNA介导的Notch1表达下调能够引起细胞周期阻滞和细胞凋亡率增加,从而抑制T-ALL细胞的增殖。
3.siRNA介导的Notch1表达下调能够增加T-ALL细胞对阿霉素的药物敏感性。
4.siRNA介导的Notch1表达下调增加细胞凋亡与药敏的机制可能与抑制Akt生存通路相关。
5.Notch1与Akt通路存在相互联系,Notch信号调节Akt信号。
第二部分
Notch1信号在基质细胞介导耐药中的作用
研究背景:
化疗耐药问题在治疗ALL和其他血液系统恶性疾患过程中日趋严重。近来,越来越多的证据表明肿瘤细胞与其微环境的相互作用导致了白血病和淋巴瘤的化疗耐药。然而,骨髓基质细胞(Bone marrow stromal cells,BMSCs)介导的肿瘤化疗耐药机制仍然不清楚。
为了阐述这个问题,我们聚焦于研究Notch受体家族,其在BMSCs及造血细胞广泛表达,并起重要作用。Notch信号传导通路是在进化过程中高度保守的信号传导系统,由Notch受体和配体组成。Notch基因编码4种跨膜蛋白分子,分别为Notch1、Notch2、Notch3和Notch 4,作为受体与相应配体(Delta-like 1、Delta-like 3、Delta-like 4、Jagged 1和Jagged 2)结合。位于细胞膜表面的Notch受体与相应配体结合后,引发分别由TACE(TNF-α-converting enzyme)和γ-secretase/presenilin complex介导的水解过程,释放其活性片段Notch-IC。Notch-IC转至细胞核内,与DNA结合蛋白CBF1/Su(H)/Lag1(CSF)结合后,激活其下游靶基因HES、Hey等的转录。
有研究结果显示Notch1在成熟细胞抑制T细胞受体诱导的凋亡,在胸腺细胞抑制地塞米松诱导的凋亡,并且在T细胞起到抗凋亡的作用。愈来愈多的证据表明存在Notch1激活的肿瘤对化疗耐药。
研究目的:
研究骨髓基质细胞对T-ALL细胞药物诱导凋亡的影响;探讨Notch1信号在基质细胞介导的耐药中的作用,以揭示T-ALL耐药机制并为白血病的耐药逆转开辟新的途径。
研究方法:
通过Ficoll分离法分离骨髓单个核细胞,体外培养扩增出BMSCs;应用脂质体介导的方法将siRNA转入T-ALL细胞株Jurkat细胞,后与间充质细胞共培养;免疫磁珠分选共培养后的白血病细胞;RQ-PCR法检测基因的表达;流式细胞术检测细胞凋亡;Western blot检测其蛋白的表达情况。
研究结果:
1.骨髓基质细胞保护Jurkat细胞药物诱导的凋亡。Jurkat细胞与基质细胞共培养,然后加入细胞毒药物,检测凋亡。共培养的Jurkat细胞与悬浮细胞培养组加入1μM地塞米松凋亡率分别为17.30%,67.91%;加入阿霉素凋亡率分别为9.46%,22.19%。
2.基质细胞表达Notch1配体,Jurkat细胞中的Notch1信号共培养后进一步激活。在共培养后检测Notch1与下游靶基因HES-1蛋白的表达。Jurkat细胞悬浮培养或与基质细胞共培养48h,共培养的Jurkat细胞与悬浮培养组比较Notch1激活形式蛋白Notch1-ICD及HES-1蛋白表达增多。
3.Western blot检测发现共培养的Jurkat细胞与悬浮培养组比较磷酸化Akt蛋白表达上升。
4.Notch1 siRNA有效下调了共培养Jurkat细胞Notch1的表达。Notch1 siRNA的效率由实时定量PCR及Western blot判定。Notchl的蛋白表达几乎被NotchlsiRNA完全敲除。HES-1蛋白的表达亦明显降低。实时定量PCR亦在mRNA水平证实Notch1 siRNA有效下调Jurkat细胞Notch1和HES-1基因的表达。
5.siRNA转染Jurkat细胞,后与基质细胞共培养,24h后加入地塞米松或阿霉素进行凋亡检测。凋亡结果显示Notch1-IC siRNA转染共培养的Jurkat细胞与siRNA对照片段转染组比较增加化疗药物地塞米松或阿霉素诱导的细胞凋亡。
6.Western blot检测结果显示干扰组磷酸化Akt蛋白表达下调。
结论:
1.骨髓基质细胞保护Jurkat细胞药物诱导的凋亡。
2.白血病细胞与基质细胞的相互作用激活Notch1-HES和Akt通路。
3.下调Notch1恢复共培养Jurkat细胞的药物敏感性,其机制涉及Akt信号通路的抑制。
Section I The effects of down-regulation of Notch1 mediated by siRNA on the proliferation and apoptosis of T-ALL cells
Background:
T-cell acute lymphoblastic leukemia (T-ALL) ranks a serious type of hematological malignancies in patients, constituting a substantial fraction of ALL, both in children and in adults. Current treatment is primarily based on combination chemotherapy with low long-term survival rate particularly in adult patients, emphasizing the need for improved therapy. A large body of evidence has been accumulated showing that oncogene activation and antioncogene inactivation can lead uncontrolled proliferation, defective differentiation and abnormal apoptosis, and then leukemias develop. The molecular mechanisms underpinning T-ALL are likely to be complex.
The involvement of Notch1 was first observed in a rare t(7;9)(q34;q34.3) translocation, which brings an activated form of the Notch-1 receptor gene under the control element of the T-cell receptor gene. More recently, it was shown that more than 50% of all T-ALL patients carried Notch1 gain-of-function mutations that generate an activated form of Notch. Mutant Notch1 could represent an important new target for therapy of T-ALL patients. Since the generation of activated Notch1 can be inhibited by gamma-secretase inhibitors (GSIs), GSIs are valuable tools for delineating the cell biological function of the Notch cascade, but the efficacy of this strategy has been questioned, as GSIs seem to be active in only a small fraction of human and mouse T-ALL cell lines with constitutive Notch1 activity. GSI are not specific for Notch1 and turn off all four Notch receptors. Furthermore, gamma-secretase might affect other proteins involved in proliferation. Therefore, it is important to explore the role of Notch1 in T-ALL using RNA interference technology.
Objective:
To investigate Notch1 on the effects of biological behavior of T-ALL cell proliferation, apoptosis and cell cycle, so as to reveal the pathogenesis of T-ALL and provide thebasis for molecular targeted therapy.
Materials and Methods:
1. Cell culture. Human T-ALL cell lines SupT1, Jurkat were cultured in RPMI medium 1640. Total RNA was extracted by Trizol according to the manufacturer's instructions. Synthesis of first-strand cDNA was carried out with Revert Aid? First Strand cDNA Synthesis Kit. RT-PCR was used to detect the expression of Notchl,HES-1 mRNA.
2. Immunocytochemical stain. SupT1 and Jurkat cells on cover slides were fixed in 95% ethanol, and then the expression of Notch1 protein was detected using Notch1 antibody according to the manufacturer's instructions.
3. SiRNA transfection. 8-16×10~5/ml of SupT1 and Jurkat cells were seeded in 24-well plates. And then cells were treated with 100nM Notch1 siRNA/control siRNA. Seventy-two hours after siRNA transfection, cells were used for MTT, real-time PCR, western blot, and other experiments.
4. Cell growth inhibition by MTT assay. SupT1 and Jurkat cells were incubated at a density of 5,000 cells/well in 96-well plates, and subsequently transfected with Notch1 siRNA or control siRNA. 24, 48, 72, 96 hours after tansfection, 20μl of MTT was added each well. 4 additional hours later, color development was measured on a microplate reader at 570 nm.
5. Flow cytometry and cell cycle analysis. Notch1 siRNA, or control siRNA transfected SupT1, Jurkat cells were collected and stained with PI. DNA content was detected on a FACS Calibur.
6. Apoptosis Assay. 72 hours after transfection, Notch1 siRNA/control siRNA transfected SupT1 and Jurkat cells were collected and were labeled with annexin V-biotin followed by PI. Annexin V/PI were measured by FACS Calibur and analyzed with the Modfit Software.
7. For the chemotherapeutic drug assays, 24 hours after transfection, cells were exposed to different concentration of adriamycin respectively for 48 hours, and then cells were collected and analyzed as above.
8. Western Blot Analysis. Total protein was extracted from transfected cells with Notch1 siRNA/control siRNA cells. Total proteins were fractionated using SDS-PAGE and transferred onto nitrocellulose membrane. After incubation with blocking buffer, the membrane was incubated with primary and secondary antibodies. The protein bands were detected using the enhanced chemiluminesence detection system.
Results:
1. Notch1 and HES-1 mRNAs were all expressed in human T-ALL cell lines SupT1 and Jurkat.
2. Immunocytochemical stain results show that Notch1 protein is expressed and located at different places in human T-ALL cell lines SupT1 and Jurkat.
3. Notch1 siRNA effectively down-regulated the expression level of Notch1 in human T-ALL cells. Notch1 and HES1 mRNAs were decreased by more than 90% in both SupT1 and Jurkat cells. Protein levels were also greatly reduced in Notch1 siRNA transfected cells compared with control siRNA transfected cells.
4. Down-regulation of Notch1 expression by siRNA inhibited the proliferation of human T-ALL cells. Cell viability was determined by the MTT assay after transfection with Notch1 siRNA or control siRNA. Down-regulation of Notch1 expression by siRNA markedly inhibited cell proliferation in SupT1 cells at 48, 72 and 96 h (P<0.05), whereas no apparent changes in Jurkat cells occurred (P> 0.05).
5. Down-regulation of Notch1 expression by siRNA induced G_0/G_1 phase cell cycle arrest in SupT1 cells. The Notch1 siRNA transfected SupT1 cells demonstrated a phase arrest pattern (62.85% vs. 46.17%) at 72 hours after transfection as compared with control cells. No alteration in cell cycle distribution was observed in Jurkat cells.
6. Down-regulation of Notch1 expression by siRNA led to apoptosis in human T-ALL cells. 72 hours after transfection, cells were stained with Annexin V/PI, and analyzed by flow cytometry. The early and late apoptosis rates were 9.01% and 12.41% in Notch1 siRNA-transfected SupT1 cells, compared with 4.13% and 4.84% in control siRNA-transfected group respectively. There was no apparent change in early and late apoptosis of Jurkat cells.
7. Down-regulation of Notch1 expression by siRNA increased chemosensitivity. We have used siRNA to specifically knock down the expression of Notch1 in SupT1 and Jurkat cells, and then examined cell viability and drug-induced apoptosis. Results showed that the IC50 value of adriamycin in SupT1 cells transfected with control siRNA was 0.21 (μg/ml) and SupT1 cells transfected with Notch1 siRNA was more sensitive, with an IC_(50) value of 0.05 (μg/ml). The combination of Notch1 siRNA and adriamycin group increased the apoptosis rate 2.4 fold in comparison with the combination of control siRNA and adriamycin group in SupT1 cells. However, there was no significant difference in Jurkat cells between the combination of Notch1 siRNA and adriamycin group and the combination of control siRNA and adriamycin group.
8. Down-regulation of Notch1 expression affected the levels of cyclin proteins and p-Akt protein. Results showed that p-Akt, cyclin D1 and CDK2 protein expressions were decreased while p21 protein expression was increased in Notch1 siRNA-transfected SupT1 cells. However, there was no significant change of the expressions of p-Akt, cyclin D1 and CDK2 proteins, and p21 protein expression was slightly increased in Notch1 siRNA-transfected Jurkat cells.
Conclusion:
1. Notch1 siRNA effectively down-regulated the expression level of Notch1.
2. Down-regulation of Notch1 mediated by siRNA can inhibit the proliferation of T-ALL cells by increasing apoptosis and inducing cell cycle arrest.
3. Down-regulation of Notch1 mediated by siRNA can increase T-ALL cells chemosensitivity to adriamycin.
4. These effects may be through the repressing of Akt pathway.
5. Notch pathway interacts with Akt pathway and Notch signaling can regulate Akt signaling.
Section II The role of Notch1 in BMSCs mediated drug resistance of T-ALL cells
Background:
Resistance to chemotherapy is one of the most serious problems in treating patients with ALL and other hematologic malignancies. Recently, increasing evidence suggests that the interaction between tumor cells and elements of their microenvironment results in resistance to chemotherapy in leukemia and myeloma. However, the molecular mechanisms of BMSCs-mediated drug resistance of tumor cells are poorly understood.
To address this question, we have focused on the Notch family of receptors and transcriptional regulators that are critically important for interaction between BMSCs and hematopoietic cells. Notch signaling is a pathway highly conserved through evolution which regulates various physiological processes, including stem cell maintenance, differentiation, proliferation and apoptosis. In mammals, key components of the Notch pathway include four transmembrane receptors (Notch 1-4) and five ligands (Delta-like 1, Delta-like 3, Delta-like 4, Jagged 1, Jagged 2). Direct binding of a ligand from a signaling cell to a Notch receptor on the membrane of the receiving cell initiates two successive proteolytic cleavages by TACE (TNF-α-converting enzyme) and theγ-secretase/presenilin complex, which ultimately results in the release of the intracellular domain (Notch-IC). Notch-IC then translocates into the nucleus and directly interacts with the DNA binding protein CBFl/Su(H)/Lagl(CSF) that activates the transcription of target genes including the HES (hairy/enhancer-of-split) and hey.
Notch1 has been shown to inhibit T-cell receptor-induced apoptosis in mature cells and dexamethasone-mediated apoptosis in thymocytes and to be antiapoptotic in T cells. More and more evidence suggests cancers with activated Notch1 signal are chemo-resistant. We suggest that Notch1 signaling may play an important role in the drug resistance mediated by stromal cells.
Objective:
To investigate BMSCs on the effect of drug-induced apoptosis of T-ALL cells and explore the role of Notch1 signaling in the drug resistance mediated by stromal cells, so as to reveal the pathogenesis of T-ALL and provide the basis for molecular targeted therapy for drug resistance.
Materials and Methods:
BMSCs were isolated and culture-expanded from human bone marrow; Jurkat cells were transfected by siRNA using the Lipofectamine 2000 reagent, and then co-cultured with BMSCs; co-cultured Jurkat cells were selected using CD3+ magnetic micro beads for real-time reverse transcription-PCR, apoptosis analysis and Western blot; real time quantitative polymerase chain reaction (RQ-PCR) was used to detect the mRNA; Flow cytometry was used to detect apoptosis; Western blot were applied to detect the protein expression.
Results:
1. BMSCs protect drug-induced apoptosis in Jurkat cells. Jurkat cells were co-cultured with BMSCs followed by cytotoxic drugs. Jurkat cells cocultured with BMSCs were resistant to dexamethasone and adriamycin treatment. Treatment of Jurkat cells with 1μM dexamethasone induced 67.91% apoptosis of cells maintained in suspension, compared with a value of 17.30% of cells co-cultured with BMSCs. Similarly, Jurkat cells contact with BMSCs followed by adriamycin also underwent less apoptosis than those in suspension (9.46% vs. 22.19%).
2. Notch1 ligands are detected in BMSCs and Notch-1 signaling is further activated in Jurkat cells following contact with BMSCs. The protein expression of Notch-1 and its target gene HES-1 were examined. Jurkat cells were incubated for 48 hours in suspension or on the monolayer of BMSCs. Notch1-ICD (the activated form of Notch1) and HES-1 protein were increased in Jurkat cells with BMSCs compared with those in suspension.
3. P-Akt is up-regulated in Jurkat cells following contact with BMSCs. Western blot analysis with antibodies specific for phosphorylated Akt was performed. Level of phosphorylated Akt was elevated in co-cultured Jurkat cells compared with that in suspension.
4. Notch1 siRNA effectively down-regulates the expression level of Notch1 in Jurkat. The efficiency of Notch1 siRNA for knockdown of Notch1 mRNA and protein was confirmed by real time RT-PCR and Western blot. Notch1 protein level was significantly reduced and almost completely knocked down by Notch1 siRNA compared with control siRNA-transfected cells in Jurkat cells. And Knock-down of Notch1 in Jurkat cells resulted in decreased protein levels of Notch target gene HES-1. Knock-down of Notch1 and HES-1 in Jurkat cells with siRNA paralleled the reduced amount of specific mRNA, as demonstrated by real time RT-PCR amplification
5. Down-regulation of Notch1 enhances the effect of chemotherapy on co-cultured Jurkat cells. Notch1 was down-regulated by siRNA in Jurkat cells, and then drug-induced apoptosis of co-cultured Jurkat cells was examined. Control siRNA-or Notch1 siRNA-transfected Jurkat cells following contact with BMSCs were exposed to dexamethasone or adriamycin as described, drug-induced apoptotic rates was detected. Notch1 siRNA-transfected Jurkat cells following contact with BMSCs were significantly susceptible to apoptosis induced by dexamethasone or adriamycin compared with control siRNA-transfected Jurkat cells following contact with BMSCs
6. Down-regulation of Notch1 affects the level of p-Akt protein. p-Akt protein was examined by Western blot analysis. When Notch1 was down-regulated in Jurkat cells following contact with BMSCs, the expression of p-Akt was decreased.
Conclusion:
1. BMSCs protect drug-induced apoptosis in Jurkat cells
2. Interactions of leukemic and BMSCs result in activation of Notch1-HES and Akt signaling in leukemic cells.
3. Down-regulation of Notch1 restores of sensitivity to chemotherapy of co-cultured Jurkat cells. The possible mechanisms of restoration of sensitivity to chemotherapy of Jurkat cells following contact with BMSCs by down-regulation of Notch1 could be associated with repressed the activity of Akt signaling.
siRNA介导的Notchl下调对T-ALL细胞增殖凋亡影响
研究背景:
T细胞急性淋巴细胞白血病(T-ALL)是一类严重威胁人类健康的血液系统恶性疾患,在儿童及成人发病率较高。目前主要采取联合化疗来治疗白血病,但患者长期生存率仍较低,尤其是在成人T-ALL亟需完善治疗措施以改善预后。白血病的发生是由于癌基因的激活,抑癌基因的失活,导致细胞异常增殖、分化障碍和凋亡受阻。涉及T-ALL发病的分子机制非常复杂。
Notch信号与肿瘤的关系最早发现于急性T淋巴细胞白血病,t(7;9)(q34;q34.3)染色体易位使9号染色体上Notch 1基因的胞内段编码区与7号染色体上T细胞受体(T cell receptor,TCR)β基因的增强子和启动子区融合,导致Notch信号组成型激活,引起了肿瘤的发生。最近有学者报道,约50%T-ALL病人存在Notchl激活的突变,说明Notchl的异常激活是T-ALL的重要发病机制。γ分泌酶抑制剂(gamma secretase inhibitor,GSI)能够有效抑制Notchl的激活,但近期多数研究报道GSI只对人或鼠的一小部分细胞株起作用。此外,GSI作用不专一,可以阻断所有Notch受体并影响其他涉及增殖的蛋白。因此,我们利用RNA干扰技术特异性下调Notch表达深入探讨Notchl在T-ALL的作用及机制。
研究目的:
研究Notchl信号对T-ALL细胞增殖、凋亡和周期等生物学行为的影响,以揭示T-ALL发病机制并为白血病的靶向治疗开辟新的途径。
研究方法:
1.体外培养T-ALL细胞系SupT1,Jurkat。Yrizo1方法提取组织总RNA,在一定的反应体系中逆转录成cDNA,PCR方法检测Notchl,HES-1在mRNA水平的表达情况。
2.免疫细胞化学染色:体外培养T-ALL细胞系SupT1和Jurkat,细胞固定后用Notch1抗体对标本进行免疫染色,以检测Notch1在T-ALL细胞中的表达情况。
3.siRNA片段的转染:取指数生长期细胞消化计数后按8.16×10~5/ml接种于24孔细胞培养板中,后应用Lipofectamine2000将针对Notch1的siRNA片段转染T-ALL细胞SupT1和Jurkat。72小时后real-time PCR方法检测siRNA片段对Notch1 mRNA表达的阻断效率。
4.MTT方法检测siRNA片段对T-ALL细胞增殖的影响:取指数生长期细胞消化计数后按5×10~3个/孔接种于96孔细胞培养板中,后转染siRNA片段。转染后24、48、72小时MTT方法检测小干扰片段对细胞增殖的影响。
5.流式细胞术检测siRNA片段对细胞周期的影响:取指数生长期细胞接种于细胞培养板中,后转染siRNA片段,转染后72小时收集细胞,PI染色后利用流式细胞仪检测细胞周期的变化。
6.流式细胞术检测siRNA片段对细胞凋亡率的影响:取指数生长期细胞接种于细胞培养板中,转染siRNA片段,转染后72小时收集细胞,AnnexinV/PI双染后利用流式细胞仪检测细胞凋亡率的变化。
7.MTT方法检测siRNA片段对T-ALL细胞化疗药物敏感性的影响:取指数生长期细胞接种于细胞培养板中,24小时后转染siRNA片段。转染后24小时加入不同浓度的化疗药物阿霉素孵育48小时,MTT检测细胞增殖情况。
8.Western blot检测通路相关蛋白表达情况:取指数生长期细胞接种于10cm培养皿,24小时后转染siRNA片段,转染后72小时收集细胞,提取细胞总蛋白,Western blot检测通路相关蛋白的表达情况。
研究结果:
1.PCR结果显示Notch1和HES-1均在T-ALL细胞系SupT1和Jurkat中表达。
2.免疫细胞化学染色方法结果显示两种细胞均存在Notch1蛋白的表达且存在不同定位。
3.针对Notch1的siRNA片段可以有效下调Notch1的表达:siRNA转染后72小时,SupT1和Jurkat细胞干扰组Notch1 mRNA的表达较对照组分别下降91.8%±4.56%和90.2%±7.84%(P＜0.05)。SupT1和Jurkat细胞干扰组Notch1蛋白亦出现明显的下调。
4.MTT检测发现在48、72及96 h,siRNA介导的Notch1的下调明显的抑制SupT1细胞的增殖(P＜0.05),而Jurkat细胞的增殖没有受到明显的影响(P＞0.05)。
5.SupT1转染siRNA后72小时,流式细胞仪检测细胞周期分布,干扰组为:G_0/G_1:62.85%,而对照组细胞的周期分布为:G_0/G_1:46.17%,与对照组比较G_0/G_1细胞增多,下调Notchl的表达能够导致SupT1的细胞周期阻滞于G_0/G_1期,而对Jurkat细胞的周期无明显作用。
6.SupT1细胞转染siRNA后72小时,AnnexinV/PI双染后流式细胞仪检测细胞凋亡率,干扰组早期、晚期凋亡率分别为9.01%、12.41%,对照组凋亡率为4.13%、4.84%;Jurkat转染siRNA后72小时,干扰组凋亡率与对照组无明显改变。下调Notch1的表达能够显著增加SupT1细胞的凋亡率。
7.SupT1和Jurkat细胞转染后24小时,加入阿霉素作用48小时。结果显示SupT1细胞干扰组与对照组阿霉素的IC50值分别为0.05μg/ml和0.21μg/ml(P＜0.05)。SupT1细胞干扰组与对照组相比阿霉素诱导的凋亡率增加了2.4倍。Jurkat细胞干扰组与对照组相比无明显差异(P＞0.05)。
8.SupT1细胞干扰组cyclin D1及CDK2蛋白出现明显的下调,p21蛋白的表达则明显增高。Jurkat细胞干扰组cyclin D1及CDK2蛋白未出现明显的改变,p21蛋白的表达略增高。SupT1细胞干扰组p-Akt蛋白明显降低,而Jurkat细胞干扰组与对照组相比无明显改变。
结论:
1.siRNA可以有效阻断Notch1的表达。
2.siRNA介导的Notch1表达下调能够引起细胞周期阻滞和细胞凋亡率增加,从而抑制T-ALL细胞的增殖。
3.siRNA介导的Notch1表达下调能够增加T-ALL细胞对阿霉素的药物敏感性。
4.siRNA介导的Notch1表达下调增加细胞凋亡与药敏的机制可能与抑制Akt生存通路相关。
5.Notch1与Akt通路存在相互联系,Notch信号调节Akt信号。
第二部分
Notch1信号在基质细胞介导耐药中的作用
研究背景:
化疗耐药问题在治疗ALL和其他血液系统恶性疾患过程中日趋严重。近来,越来越多的证据表明肿瘤细胞与其微环境的相互作用导致了白血病和淋巴瘤的化疗耐药。然而,骨髓基质细胞(Bone marrow stromal cells,BMSCs)介导的肿瘤化疗耐药机制仍然不清楚。
为了阐述这个问题,我们聚焦于研究Notch受体家族,其在BMSCs及造血细胞广泛表达,并起重要作用。Notch信号传导通路是在进化过程中高度保守的信号传导系统,由Notch受体和配体组成。Notch基因编码4种跨膜蛋白分子,分别为Notch1、Notch2、Notch3和Notch 4,作为受体与相应配体(Delta-like 1、Delta-like 3、Delta-like 4、Jagged 1和Jagged 2)结合。位于细胞膜表面的Notch受体与相应配体结合后,引发分别由TACE(TNF-α-converting enzyme)和γ-secretase/presenilin complex介导的水解过程,释放其活性片段Notch-IC。Notch-IC转至细胞核内,与DNA结合蛋白CBF1/Su(H)/Lag1(CSF)结合后,激活其下游靶基因HES、Hey等的转录。
有研究结果显示Notch1在成熟细胞抑制T细胞受体诱导的凋亡,在胸腺细胞抑制地塞米松诱导的凋亡,并且在T细胞起到抗凋亡的作用。愈来愈多的证据表明存在Notch1激活的肿瘤对化疗耐药。
研究目的:
研究骨髓基质细胞对T-ALL细胞药物诱导凋亡的影响;探讨Notch1信号在基质细胞介导的耐药中的作用,以揭示T-ALL耐药机制并为白血病的耐药逆转开辟新的途径。
研究方法:
通过Ficoll分离法分离骨髓单个核细胞,体外培养扩增出BMSCs;应用脂质体介导的方法将siRNA转入T-ALL细胞株Jurkat细胞,后与间充质细胞共培养;免疫磁珠分选共培养后的白血病细胞;RQ-PCR法检测基因的表达;流式细胞术检测细胞凋亡;Western blot检测其蛋白的表达情况。
研究结果:
1.骨髓基质细胞保护Jurkat细胞药物诱导的凋亡。Jurkat细胞与基质细胞共培养,然后加入细胞毒药物,检测凋亡。共培养的Jurkat细胞与悬浮细胞培养组加入1μM地塞米松凋亡率分别为17.30%,67.91%;加入阿霉素凋亡率分别为9.46%,22.19%。
2.基质细胞表达Notch1配体,Jurkat细胞中的Notch1信号共培养后进一步激活。在共培养后检测Notch1与下游靶基因HES-1蛋白的表达。Jurkat细胞悬浮培养或与基质细胞共培养48h,共培养的Jurkat细胞与悬浮培养组比较Notch1激活形式蛋白Notch1-ICD及HES-1蛋白表达增多。
3.Western blot检测发现共培养的Jurkat细胞与悬浮培养组比较磷酸化Akt蛋白表达上升。
4.Notch1 siRNA有效下调了共培养Jurkat细胞Notch1的表达。Notch1 siRNA的效率由实时定量PCR及Western blot判定。Notchl的蛋白表达几乎被NotchlsiRNA完全敲除。HES-1蛋白的表达亦明显降低。实时定量PCR亦在mRNA水平证实Notch1 siRNA有效下调Jurkat细胞Notch1和HES-1基因的表达。
5.siRNA转染Jurkat细胞,后与基质细胞共培养,24h后加入地塞米松或阿霉素进行凋亡检测。凋亡结果显示Notch1-IC siRNA转染共培养的Jurkat细胞与siRNA对照片段转染组比较增加化疗药物地塞米松或阿霉素诱导的细胞凋亡。
6.Western blot检测结果显示干扰组磷酸化Akt蛋白表达下调。
结论:
1.骨髓基质细胞保护Jurkat细胞药物诱导的凋亡。
2.白血病细胞与基质细胞的相互作用激活Notch1-HES和Akt通路。
3.下调Notch1恢复共培养Jurkat细胞的药物敏感性,其机制涉及Akt信号通路的抑制。
Section I The effects of down-regulation of Notch1 mediated by siRNA on the proliferation and apoptosis of T-ALL cells
Background:
T-cell acute lymphoblastic leukemia (T-ALL) ranks a serious type of hematological malignancies in patients, constituting a substantial fraction of ALL, both in children and in adults. Current treatment is primarily based on combination chemotherapy with low long-term survival rate particularly in adult patients, emphasizing the need for improved therapy. A large body of evidence has been accumulated showing that oncogene activation and antioncogene inactivation can lead uncontrolled proliferation, defective differentiation and abnormal apoptosis, and then leukemias develop. The molecular mechanisms underpinning T-ALL are likely to be complex.
The involvement of Notch1 was first observed in a rare t(7;9)(q34;q34.3) translocation, which brings an activated form of the Notch-1 receptor gene under the control element of the T-cell receptor gene. More recently, it was shown that more than 50% of all T-ALL patients carried Notch1 gain-of-function mutations that generate an activated form of Notch. Mutant Notch1 could represent an important new target for therapy of T-ALL patients. Since the generation of activated Notch1 can be inhibited by gamma-secretase inhibitors (GSIs), GSIs are valuable tools for delineating the cell biological function of the Notch cascade, but the efficacy of this strategy has been questioned, as GSIs seem to be active in only a small fraction of human and mouse T-ALL cell lines with constitutive Notch1 activity. GSI are not specific for Notch1 and turn off all four Notch receptors. Furthermore, gamma-secretase might affect other proteins involved in proliferation. Therefore, it is important to explore the role of Notch1 in T-ALL using RNA interference technology.
Objective:
To investigate Notch1 on the effects of biological behavior of T-ALL cell proliferation, apoptosis and cell cycle, so as to reveal the pathogenesis of T-ALL and provide thebasis for molecular targeted therapy.
Materials and Methods:
1. Cell culture. Human T-ALL cell lines SupT1, Jurkat were cultured in RPMI medium 1640. Total RNA was extracted by Trizol according to the manufacturer's instructions. Synthesis of first-strand cDNA was carried out with Revert Aid? First Strand cDNA Synthesis Kit. RT-PCR was used to detect the expression of Notchl,HES-1 mRNA.
2. Immunocytochemical stain. SupT1 and Jurkat cells on cover slides were fixed in 95% ethanol, and then the expression of Notch1 protein was detected using Notch1 antibody according to the manufacturer's instructions.
3. SiRNA transfection. 8-16×10~5/ml of SupT1 and Jurkat cells were seeded in 24-well plates. And then cells were treated with 100nM Notch1 siRNA/control siRNA. Seventy-two hours after siRNA transfection, cells were used for MTT, real-time PCR, western blot, and other experiments.
4. Cell growth inhibition by MTT assay. SupT1 and Jurkat cells were incubated at a density of 5,000 cells/well in 96-well plates, and subsequently transfected with Notch1 siRNA or control siRNA. 24, 48, 72, 96 hours after tansfection, 20μl of MTT was added each well. 4 additional hours later, color development was measured on a microplate reader at 570 nm.
5. Flow cytometry and cell cycle analysis. Notch1 siRNA, or control siRNA transfected SupT1, Jurkat cells were collected and stained with PI. DNA content was detected on a FACS Calibur.
6. Apoptosis Assay. 72 hours after transfection, Notch1 siRNA/control siRNA transfected SupT1 and Jurkat cells were collected and were labeled with annexin V-biotin followed by PI. Annexin V/PI were measured by FACS Calibur and analyzed with the Modfit Software.
7. For the chemotherapeutic drug assays, 24 hours after transfection, cells were exposed to different concentration of adriamycin respectively for 48 hours, and then cells were collected and analyzed as above.
8. Western Blot Analysis. Total protein was extracted from transfected cells with Notch1 siRNA/control siRNA cells. Total proteins were fractionated using SDS-PAGE and transferred onto nitrocellulose membrane. After incubation with blocking buffer, the membrane was incubated with primary and secondary antibodies. The protein bands were detected using the enhanced chemiluminesence detection system.
Results:
1. Notch1 and HES-1 mRNAs were all expressed in human T-ALL cell lines SupT1 and Jurkat.
2. Immunocytochemical stain results show that Notch1 protein is expressed and located at different places in human T-ALL cell lines SupT1 and Jurkat.
3. Notch1 siRNA effectively down-regulated the expression level of Notch1 in human T-ALL cells. Notch1 and HES1 mRNAs were decreased by more than 90% in both SupT1 and Jurkat cells. Protein levels were also greatly reduced in Notch1 siRNA transfected cells compared with control siRNA transfected cells.
4. Down-regulation of Notch1 expression by siRNA inhibited the proliferation of human T-ALL cells. Cell viability was determined by the MTT assay after transfection with Notch1 siRNA or control siRNA. Down-regulation of Notch1 expression by siRNA markedly inhibited cell proliferation in SupT1 cells at 48, 72 and 96 h (P<0.05), whereas no apparent changes in Jurkat cells occurred (P> 0.05).
5. Down-regulation of Notch1 expression by siRNA induced G_0/G_1 phase cell cycle arrest in SupT1 cells. The Notch1 siRNA transfected SupT1 cells demonstrated a phase arrest pattern (62.85% vs. 46.17%) at 72 hours after transfection as compared with control cells. No alteration in cell cycle distribution was observed in Jurkat cells.
6. Down-regulation of Notch1 expression by siRNA led to apoptosis in human T-ALL cells. 72 hours after transfection, cells were stained with Annexin V/PI, and analyzed by flow cytometry. The early and late apoptosis rates were 9.01% and 12.41% in Notch1 siRNA-transfected SupT1 cells, compared with 4.13% and 4.84% in control siRNA-transfected group respectively. There was no apparent change in early and late apoptosis of Jurkat cells.
7. Down-regulation of Notch1 expression by siRNA increased chemosensitivity. We have used siRNA to specifically knock down the expression of Notch1 in SupT1 and Jurkat cells, and then examined cell viability and drug-induced apoptosis. Results showed that the IC50 value of adriamycin in SupT1 cells transfected with control siRNA was 0.21 (μg/ml) and SupT1 cells transfected with Notch1 siRNA was more sensitive, with an IC_(50) value of 0.05 (μg/ml). The combination of Notch1 siRNA and adriamycin group increased the apoptosis rate 2.4 fold in comparison with the combination of control siRNA and adriamycin group in SupT1 cells. However, there was no significant difference in Jurkat cells between the combination of Notch1 siRNA and adriamycin group and the combination of control siRNA and adriamycin group.
8. Down-regulation of Notch1 expression affected the levels of cyclin proteins and p-Akt protein. Results showed that p-Akt, cyclin D1 and CDK2 protein expressions were decreased while p21 protein expression was increased in Notch1 siRNA-transfected SupT1 cells. However, there was no significant change of the expressions of p-Akt, cyclin D1 and CDK2 proteins, and p21 protein expression was slightly increased in Notch1 siRNA-transfected Jurkat cells.
Conclusion:
1. Notch1 siRNA effectively down-regulated the expression level of Notch1.
2. Down-regulation of Notch1 mediated by siRNA can inhibit the proliferation of T-ALL cells by increasing apoptosis and inducing cell cycle arrest.
3. Down-regulation of Notch1 mediated by siRNA can increase T-ALL cells chemosensitivity to adriamycin.
4. These effects may be through the repressing of Akt pathway.
5. Notch pathway interacts with Akt pathway and Notch signaling can regulate Akt signaling.
Section II The role of Notch1 in BMSCs mediated drug resistance of T-ALL cells
Background:
Resistance to chemotherapy is one of the most serious problems in treating patients with ALL and other hematologic malignancies. Recently, increasing evidence suggests that the interaction between tumor cells and elements of their microenvironment results in resistance to chemotherapy in leukemia and myeloma. However, the molecular mechanisms of BMSCs-mediated drug resistance of tumor cells are poorly understood.
To address this question, we have focused on the Notch family of receptors and transcriptional regulators that are critically important for interaction between BMSCs and hematopoietic cells. Notch signaling is a pathway highly conserved through evolution which regulates various physiological processes, including stem cell maintenance, differentiation, proliferation and apoptosis. In mammals, key components of the Notch pathway include four transmembrane receptors (Notch 1-4) and five ligands (Delta-like 1, Delta-like 3, Delta-like 4, Jagged 1, Jagged 2). Direct binding of a ligand from a signaling cell to a Notch receptor on the membrane of the receiving cell initiates two successive proteolytic cleavages by TACE (TNF-α-converting enzyme) and theγ-secretase/presenilin complex, which ultimately results in the release of the intracellular domain (Notch-IC). Notch-IC then translocates into the nucleus and directly interacts with the DNA binding protein CBFl/Su(H)/Lagl(CSF) that activates the transcription of target genes including the HES (hairy/enhancer-of-split) and hey.
Notch1 has been shown to inhibit T-cell receptor-induced apoptosis in mature cells and dexamethasone-mediated apoptosis in thymocytes and to be antiapoptotic in T cells. More and more evidence suggests cancers with activated Notch1 signal are chemo-resistant. We suggest that Notch1 signaling may play an important role in the drug resistance mediated by stromal cells.
Objective:
To investigate BMSCs on the effect of drug-induced apoptosis of T-ALL cells and explore the role of Notch1 signaling in the drug resistance mediated by stromal cells, so as to reveal the pathogenesis of T-ALL and provide the basis for molecular targeted therapy for drug resistance.
Materials and Methods:
BMSCs were isolated and culture-expanded from human bone marrow; Jurkat cells were transfected by siRNA using the Lipofectamine 2000 reagent, and then co-cultured with BMSCs; co-cultured Jurkat cells were selected using CD3+ magnetic micro beads for real-time reverse transcription-PCR, apoptosis analysis and Western blot; real time quantitative polymerase chain reaction (RQ-PCR) was used to detect the mRNA; Flow cytometry was used to detect apoptosis; Western blot were applied to detect the protein expression.
Results:
1. BMSCs protect drug-induced apoptosis in Jurkat cells. Jurkat cells were co-cultured with BMSCs followed by cytotoxic drugs. Jurkat cells cocultured with BMSCs were resistant to dexamethasone and adriamycin treatment. Treatment of Jurkat cells with 1μM dexamethasone induced 67.91% apoptosis of cells maintained in suspension, compared with a value of 17.30% of cells co-cultured with BMSCs. Similarly, Jurkat cells contact with BMSCs followed by adriamycin also underwent less apoptosis than those in suspension (9.46% vs. 22.19%).
2. Notch1 ligands are detected in BMSCs and Notch-1 signaling is further activated in Jurkat cells following contact with BMSCs. The protein expression of Notch-1 and its target gene HES-1 were examined. Jurkat cells were incubated for 48 hours in suspension or on the monolayer of BMSCs. Notch1-ICD (the activated form of Notch1) and HES-1 protein were increased in Jurkat cells with BMSCs compared with those in suspension.
3. P-Akt is up-regulated in Jurkat cells following contact with BMSCs. Western blot analysis with antibodies specific for phosphorylated Akt was performed. Level of phosphorylated Akt was elevated in co-cultured Jurkat cells compared with that in suspension.
4. Notch1 siRNA effectively down-regulates the expression level of Notch1 in Jurkat. The efficiency of Notch1 siRNA for knockdown of Notch1 mRNA and protein was confirmed by real time RT-PCR and Western blot. Notch1 protein level was significantly reduced and almost completely knocked down by Notch1 siRNA compared with control siRNA-transfected cells in Jurkat cells. And Knock-down of Notch1 in Jurkat cells resulted in decreased protein levels of Notch target gene HES-1. Knock-down of Notch1 and HES-1 in Jurkat cells with siRNA paralleled the reduced amount of specific mRNA, as demonstrated by real time RT-PCR amplification
5. Down-regulation of Notch1 enhances the effect of chemotherapy on co-cultured Jurkat cells. Notch1 was down-regulated by siRNA in Jurkat cells, and then drug-induced apoptosis of co-cultured Jurkat cells was examined. Control siRNA-or Notch1 siRNA-transfected Jurkat cells following contact with BMSCs were exposed to dexamethasone or adriamycin as described, drug-induced apoptotic rates was detected. Notch1 siRNA-transfected Jurkat cells following contact with BMSCs were significantly susceptible to apoptosis induced by dexamethasone or adriamycin compared with control siRNA-transfected Jurkat cells following contact with BMSCs
6. Down-regulation of Notch1 affects the level of p-Akt protein. p-Akt protein was examined by Western blot analysis. When Notch1 was down-regulated in Jurkat cells following contact with BMSCs, the expression of p-Akt was decreased.
Conclusion:
1. BMSCs protect drug-induced apoptosis in Jurkat cells
2. Interactions of leukemic and BMSCs result in activation of Notch1-HES and Akt signaling in leukemic cells.
3. Down-regulation of Notch1 restores of sensitivity to chemotherapy of co-cultured Jurkat cells. The possible mechanisms of restoration of sensitivity to chemotherapy of Jurkat cells following contact with BMSCs by down-regulation of Notch1 could be associated with repressed the activity of Akt signaling.
引文
1.Majer M,Jensen RL,Shrieve DC,et al.Biochemotherapy of metastatic melanoma in patients with or without recently diagnosed brain metastases.Cancer.2007;110(6):1329-37.
2.Dear R,Wilcken N,Shannon J,et al.Beyond chemotherapy—demystifying the new 'targeted' cancer treatments.Aust Fam Physician.2004;37(1-2):45-49.
3.D'Addario G,Rauch D,Stupp R,et al.Multicenter phase Ⅱ trial of gefitinib first-line therapy followed by chemotherapy in advanced non-small-cell lung cancer(NSCLC):SAKK protocol 19/03.Ann Oncol.2008;19(4):739-45.
4.Gajraj E,Chung H,Longson C,et al.Rituximab for follicular non-Hodgkin lymphoma.Lancet Oncol.2008;9(4):320-1.
5.Egan SE,St-Pierre B,Leow CC.Notch receptors,partners and regulators:from conserved domains to powerful functions.Curr Top Microbiol Immunol.1998;228:273-324.
6.Artavanis-Tsakonas S,Rand MD,Lake RJ.Notch signaling:cell fate control and signal integration in development.Science.1999;284:770-776.
7.Callahan R,Egan SE.Notch signaling in mammary development and oncogenesis.Mammary Gland Biol Neoplasia.2004;9:145-163.
8.Dontu G,AL-Hajj M,Abdallah WM,Clarke MF,Wicha MS.Stem cells in normal breast development and breast cancer.Cell Prolif.2003;36 Suppl 1:59-72.
9.Dontu G,Jackson KW,McNicholas E,Kawamura MJ,Abdallah WM,Wicha MS.Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells.Breast Cancer Res.2004;6:R605-615.
10.叶静静,马道新,赵建强,纪春岩.四种Notch配体信号功能活性比较.山东医药.2004;44(7):13-15.
11.Kopan R.Notch:a membrane-bound transcription factor.Cell Sci.2002;115:1095-1097.
12.Lai EC.Keeping a good pathway down:transcriptional repression of Notch pathway target genes by CSL proteins.EMBO Rep.2002;3:840-845.
13. Fortini ME, Artavanis-Taskonas S. The suppressor of hairless protein participates in Notch receptor signaling. Cell. 1994;79:273-282.
14. Honjo T. The shortest path from the surface to the nucleus: RBPJK/Su(H) transcription factor. Genes Cell. 1996;1:1-9.
15. Ellisen LW, Bird J, West DC, et al. TAN 1, the human homolog of the Drosophila notch gone, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell. 1991;66(4): 649-661.
16. Aster JC, Xu L, Karnell FG, Patriub V, Pui JC, Pear WS. Essential roles for ankyrin repeat and transactivation domains in induction of T-cell leukemia by notchl. Mol Cell Biol. 2000;20(20):7505-15
17. Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306:269-71.
18. Zhu YM, Zhao WL, Fu JF, et al. NOTCH1 mutations in T-cell acute lymphoblastic leukemia: prognostic significance and implication in ultifactorial leukemogenesis. Clin Cancer Res. 2006;12:3043-9.
19. Capobianco AJ, Zagouras P, Blaumueller CM, Artavanis-Tsakonas S, Bishop JM. Neoplastic transformation by truncated alleles of human NOTCH1/TAN1 and N0TCH2. Mol Cell Biol. 1997;17(11):6265-73
20. Bellavia D, Campese AF, Checquolo S, et al. Combined expression of pTalpha and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis. Proc Natl Acad Sci U S A. 2002;99(6):3788-93.
21. Lipardi C, Wei Q, Paterson BM. RNAi as random degradeative PCR. SiRNA primers convert mRNA into dsRNAs that are degraded to generate new siRNAs. Cell. 2001;107:297-307.
22. Nishikura K. A Short primer on RNAi. RNA-directed RNA polymerase acts as a key catalyst. Cell. 2001;107:415-418.
23. Caplen NJ, Parrish S, Imani F, et al. Specific inhibition of gene expression by small double-stranded RNAs in invertebrate and vertebrate systems [J]. Proc Natl Acad Sci USA. 2001;98:9742-9747.
24. Wharton KA, Johansen KM, Xu T, et al. Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell. 1985;43(3Pt2):567-581.
25. Lieber T, Kidd S, Alcamo E, et al. Antineurogenic phenotypes induced by truncated Notch proteins indicate a role in signal transduction and may point to a novel function for Notch in nuclei. Genes Dev. 1993;7 (10): 1949-1965.
26. Struhl G, Fitzgerald K, Greenwald I. Intrinsic activity of the Lin 12 and Notch intracellular domains in vivo. Cell. 1993;74 (2):331-345.
27. Logeat F, Bessia C, Brou C, et al. The Notchl receptor is cleaved constitutively by a furin-like convertase. Proc Natl Acad Sci USA. 1998;95 (14):8108-8112.
28. Artavanis Tsakonas S, Matsuno K, Fortini ME. Notch signaling. Science. 1995;268 (5208):225-232.
29. Zagouras P, Stifani S, Blaumueller CM, et al. Alterations in Notch signaling in neoplastic lesions of the human cervix. Proc Natl Acad Sci USA. 1995;92 (14):6414-6418.
30. Leethanakul C, Patel V, Gillespie J, et al. Distinct pattern of expression of differentiation and growth-related genes in squamous cell carcinomas of the head and neck revealed by the use of laser capture micro dissection and cDNA arrays. Oncogene. 2000;19(28):3220-3224.
31. Enlund F, Behboudi A, Andren Y, et al. Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors. Exp Cell Res. 2004;292(1):21-28.
32. Jundt F, Schulze Proebsting KS, Anagnostopoulos I, et al. Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells. Blood. 2004; 103(9):3511-3515.
33. Gray GE, Mann RS, Mitsiadis E, et al. Human ligands of the Notch receptor. Am J Patho1.1999; 154(3):785-794.
34. Zagouras P, Stifani S, Blaumueller CM, et al. Alterations in Notch signaling in neoplastic lesions of the human cervix. Proc Natl Acad Sci U S A. 1995;92(14):6414-6418.
35. Miyamoto Y, Maitra A, Ghosh B, et al. Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell.2003;3(6):565-576.
36. Cuevas IC, Slocum AL, Jun P, et al. Meningioma transcript profiles reveal deregulated Notch signaling pathway. Cancer Res.2005;65(12):5070-5075.
37. Purow BW, Haque RM, Noel MW, et al. Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res. 2005;65(6):2353-2363.
38. Jundt F, Anagnostopoulos I, Forster R, et al. Activated Notchl signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma. Blood. 2002;99(9):3398-3403.
39. Houde C, Li Y, Song L, et al. Overexpression of the NOTCH ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines. Blood. 2004;104(12):3697-3704.
40. Jundt F, Probsting KS, Anagnostopoulos I, et al. Jaggedl-induced Notch signaling drives proliferation of multiple myeloma cells. Blood. 2004;103(9):3511-3515.
41. Tohda S, Nara N. Expression of Notchl and Jaggedl proteins in acute myeloid leukemia cells. Leuk Lymphoma. 2001;42(3):467-472.
42. Kogoshi H, Sato T, Koyama T, et al. Gamma-secretase inhibitors suppress the growth of leukemia and lymphoma cells. Oncol Rep. 2007;18(1):77-80.
43. Nefedova Y, Sullivan DM, Bolick SC, et al. Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy. Blood. 2008;111(4):2220-2229.
44. Siemers ER, Dean RA, Friedrich S, et al. Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase. Clin Neuropharmacol. 2007;30(6):317-325.
45. Palomero T, Sulis ML, Cortina M, et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med. 2007;13:1203-1210.
46. Palomero T, Lim WK, Odom DT, et al. NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci U S A. 2006;103:18261-18266.
47. Sharma VM, Calvo JA, Draheim KM, et al. Notch1 Contributes to Mouse T-Cell Leukemia by Directly Inducing the Expression of c-myc. Mol Cell Biol. 2006;26:8022-8031.
48. Yan S, Wenner CE. Modulation of CyclinD1 and its signaling components by the phorbol ester TPA and the tyrosine phosphatase inhibitor vanadate. Cell Physiol. 2001; 186:338-349.
49. Kato J. Induction of S phase by G1 regulatory factors. Front Biosci. 1999;4:D787-92.
50. Cook SJ, Balmanno K, Garner A, Millar T, Taverner C, Todd D. Regulation of cell cycle re-entry by growth, survival and stress signalling pathways. Biochem Soc Trans. 2000;28(2):233-240.
51. Park US, Park SK, Lee YI, Park JG, Lee YI. Hepatitis B virus-X protein upregulates the expression of p21waf1/cip1 and prolongs G1-->S transition via a p53-independent pathway in human hepatoma cells. Oncogene. 2000;19(30):3384-3394.
52. Stewart ZA, Pietenpol JA. p53 Signaling and cell cycle checkpoints. Chem Res Toxicol. 2001;14(3):243-263.
53. Mungamuri SK, Yang X, Thor AD, Somasundaram K. Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53. Cancer Res. 2006; 66:4715-4724.
54. Henning K, Heering J, Schwanbeck R, et al. Notch1 activation reduces proliferation in the multipotent hematopoietic progenitor cell line FDCP-mix through a p53-dependent pathway but Notch1 effects on myeloid and erythroid differentiation are independent of p53. Cell Death Differ. 2008;15:398-407.
55. Zhang W, Funk WD, Wright WE, Shay JW, Deisseroth AB. Novel DNA binding of p53 mutants and their role in transcriptional activation. Oncogene. 1993;8(9):2555-9.
56. Cully M, You H, Levine AJ, et al. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer. 2006;6:184-192.
57. Rosen N, She QB. AKT and cancer--is it all mTOR? Cancer Cell. 2006;10:254-256.
58. Urano J, Sato T, Matsuo T, et al. Point mutations in TOR confer Rheb-independent growth in fission yeast and nutrient-independent mammalian TOR signaling in mammalian cells. Proc Natl Acad Sci U S A. 2007;104:3514-3519.
59. Takahashi K, Murakami M, Yamanaka S. Role of the phosphoinositide 3-kinase pathway in mouse embryonic stem (ES) cells. Biochem Soc Trans. 2005;33:1522-1525.
60. Zhang H, Bajraszewski N, Wu E, et al. PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. J Clin Invest. 2007; 117:730-738.
61. Saal LH, Holm K, Maurer M, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005;65:2554-2559.
62. Robertson GP. Functional and therapeutic significance of Akt deregulation in malignant melanoma. Cancer Metastasis Rev. 2005;24:273-285.
63. Gutierrez A, Look AT. NOTCH and PI3K-AKT pathways intertwined. Cancer Cell. 2007;12:411-413.
64. Calzavara E, Chiaramonte R, Cesana D, Basile A, Sherbet GV, Comi P. Reciprocal regulation of Notch and PI3K/Akt signalling in T-ALL cells In Vitro. J Cell Biochem. 2008;103:1405-1412.
65. Palomero T, Sulis ML, Cortina M, et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med. 2007;13:1203-1210.
66. Breit S, Stanulla M, Flohr T, et al. Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia. Blood. 2006;108:1151-1157.
67. Lones MA, Heerema NA, Le Beau MM, et al. Chromosome abnormalities in advanced stage lymphoblastic lymphoma of children and adolescents: a report from CCG-E08. Cancer Genet Cytogenet. 2007; 172:1-11.
68. van Grotel M, Meijerink JP, van Wering ER, et al. Prognostic significance of molecular-cytogenetic abnormalities in pediatric T-ALL is not explained by immunophenotypic differences. Leukemia. 2008;22:124-131.
1. Tavor S, Eisenbach M, Jacob-Hirsch J, et al. The CXCR4 antagonist AMD3100 impairs survival of human AML cells and induces their differentiation. Leukemia. 2008;22(12):2151-2158.
2. Gallay N, Anani L, Lopez A, et al. The role of platelet/endothelial cell adhesion molecule 1 (CD31) and CD38 antigens in marrow microenvironmental retention of acute myelogenous leukemia cells. Cancer Res. 2007;67(18):8624-8632.
3. Lwin T, Hazlehurst LA, Li Z, et al. Bone marrow stromal cells prevent apoptosis of lymphoma cells by upregulation of anti-apoptotic proteins associated with activation of NF-kappaB (RelB/p52) in non-Hodgkin's lymphoma cells. Leukemia. 2007;21(7): 1521-1531.
4. Gibson LF. Survival of B lineage leukemic cells: signals from the bone marrow microenvironment. Leuk Lymphoma. 2002;43(1):19-27.
5. Liang R, Huang GS, Wang Z, et al. Effects of human bone marrow stromal cell line (HFCL) on the proliferation, differentiation and apoptosis of acute myeloid leukemia cell lines U937, HL-60 and HL-60/VCR. Int J Hematol. 2008;87:152-166.
6. Nefedova Y, Cheng P, Alsina M, Dalton WS, Gabrilovich DI. Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Blood. 2004;103:3503-3510.
7. Konopleva M, Konoplev S, Hu W, Zaritskey AY, Afanasiev BV, Andreeff M. Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins. Leukemia. 2002;16(9):1713-1724.
8. Lagneaux L, Delforge A, Bron D, De Bruyn C, Stryckmans P. Chronic lymphocytic leukemic B cells but not normal B cells are rescued from apoptosis by contact with normal bone marrow stromal cells. Blood. 1998;91(7):2387-2396.
9. Iwamoto S, Mihara K, Downing JR, Pui CH, Campana D. Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase. J Clin Invest. 2007; 117:1049-1057.
10.梁蓉,黄高昇,陈协群,等.骨髓成纤维样基质细胞系对急性髓细胞白血病细胞系增殖与分化影响的研究.中华肿瘤防治杂志.2007;14:1281-1285.
11.Liang R,Huang GS,Wang Z,et al.Effects of human bone marrow stromal cell line(HFCL)on the proliferation,differentiation and apoptosis of acute myeloid leukemia cell lines U937,HL-60 and HL-60/VCR.Int J Hematol.2008;87(2):152-166.
12.Wang LH,Yang XY,Zhang X,Farrar WL.Inhibition of adhesive interaction between multiple myeloma and bone marrow stromal cells by PPARgamma cross talk with NF-kappaB and C/EBP.Blood.2007;110(13):4373-4384.
13.Tabe Y,Jin L,Tsutsumi-Ishii Y,et al.Activation of integrin-linked kinase is a critical prosurvival pathway induced in leukemic cells by bone marrow-derived stromal cells.Cancer Res.2007;67(2):684-694.
14.Kobune M,Chiba H,Kato J,et al.Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism.Mol Cancer Ther.2007;6(6):1774-1784.
15.Mahlknecht U,Sch(o|¨)nbein C.Histone deacetylase inhibitor treatment downregulates VLA-4 adhesion in hematopoietic stem cells and acute myeloid leukemia blast cells.Haematologica.2008;93(3):443-446.
16.Schmidmaier R,M(o|¨)rsdorf K,Baumann P,Emmerich B,Meinhardt G.Evidence for cell adhesion-mediated drug resistance of multiple myeloma cells in vivo.Int J Biol Markers.2006;21(4):218-222.
17.Kopan R.Notch:a membrane-bound transcription factor.Cell Sci.2002;115:1095-1097.
18.DeJoussineau C,Soule J,Martin M,AnguilleC,Montcourrier P,AlexandreD.Delta-promoted filopodia mediate long-range lateral inhibition in Drosophila.Nature.2003;426(6966):555-559.
19.Struhl G,Adachi A.Requirements for presenilin-dependent cleavage of notch and other transmembrane proteins.Mol Cell.2000;6(3):625-636.
20.Artavanis-Tsakonas S,Rand MD,Lake RJ.Notch signaling:cell fate control and signal integration in development.Science.1999;284:770-776.
21. Jang J, Choi YI, Choi J, Lee KY, Chung H, Jeon SH, et al. Notch1 confers thymocytes a resistance to GC-induced apoptosis through Deltexl by blocking the recruitment of p300 to the SRG3 promoter. Cell Death Differ. 2006;13:1495-1505.
22. Sade H, Krishna S, Sarin A. The anti-apoptotic effect of Notch-1 requires p56~(lck)-dependent, Akt/PKB-mediated signaling in T cells. J Biol Chem 2004;279:2937-2944.
23. Kogoshi H, Sato T, Koyama T, Nara N, Tohda S. Gamma-secretase inhibitors suppress the growth of leukemia and lymphoma cells. Oncol Rep. 2007;18(1):77-80.
24. Mungamuri SK, Yang X, Thor AD, Somasundaram K. Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53. Cancer Res. 2006; 66(9):4715-4724.
25. Nefedova Y, Sullivan DM, Bolick SC, et al. Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy. Blood. 2008; 111 (4):2220-2229.
26. Rangarajan A, Syal R, Selvarajah S, Chakrabarti 0, Sarin A, Krishna S. Activated Notch1 signaling cooperates with papillomavirus oncogenes in transformation and generates resistance to apoptosis on matrix withdrawal through PKB/Akt. Virology. 2001 ;286:23-30.
27. Nair P, Somasundaram K, Krishna S. Activated Notch1 inhibits p53-induced apoptosis and sustains transformation by human papillomavirus type 16 E6 and E7 oncogenes through a PI3K-PKB/Akt-dependent pathway. J Virol. 2003;77:7106-7112.
28. Bheeshmachar G, Purushotaman D, Sade H, Gunasekharan V, Rangarajan A, Sarin A. Evidence for a role for notch signaling in the cytokine-dependent survival of activated T cells. J Immunol 2006; 177:5041-5050.
29. Gutierrez A, Look AT. NOTCH and PI3K-AKT pathways intertwined. Cancer Cell. 2007;12:411-413.
30. Calzavara E, Chiaramonte R, Cesana D, Basile A, Sherbet GV, Comi P. Reciprocal regulation of Notch and PI3K/Akt signalling in T-ALL cells In Vitro. J Cell Biochem. 2008;103:1405-1412.
31. Maliekal TT, Bajaj J, Giri V, Subramanyam D, Krishna S. The role of Notch signaling in human cervical cancer: implications for solid tumors. Oncogene. 2008;27(38):5110-5114.
32. Liu ZJ, Xiao M, Balint K, et al. Inhibition of endothelial cell proliferation by Notch1 signaling is mediated by repressing MAPK and PI3K/Akt pathways and requires MAML1. FASEB J. 2006;20(7): 1009-1011.
33. Foltz DR, Santiago MC, Berechid BE, Nye JS. Glycogen synthase kinase-3beta modulates notch signaling and stability. Curr Biol. 2002;12:1006-1011.
34. Bedogni B, Warneke JA, Nickoloff BJ, Giaccia AJ, Powell MB. J Clin Invest. Notch1 is an effector of Akt and hypoxia in melanoma development. J Clin Invest. 2008;118(11):3660-3670.
1. Artavanis-Tsakonas S, Matsuno K, Fortini ME. Notch signaling. Science 1995;268:225-32.
2. Greenwald I. LIN-12/Notch signaling: lessons from worms and flies. Genes Dev 1998; 12:1751-62.
3. Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, et al. TAN-1, the human homolog of the Drosophila notch gene isbroken by chromosomal translocations in T lymphoblastic neoplasms. Cell 1991;66:649-61.
4. Weng AP, Ferrando AA, Lee W, Morris JP 4th, Silverman LB, Sanchez-Irizarry C, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004;306:269-71.
5. Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M, et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 2007;13(10):1203-10.
6. O'Neil J, Grim J, Strack P, Rao S, Tibbitts D, Winter C, et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitorsJ Exp Med 2007;204(8): 1813-24.
7. Godfrey DI, Zlotnik A. Control points in early T-cell development. Immunol Today 1993;14:547-53.
8. Weerkamp F, de Haas EF, Naber BA, Comans-Bitter WM, Bogers AJ, van Dongen JJ et al. Age-related changes in the cellular composition of the thymus in children. J Allergy Clin Immunol 2005; 115:834-40.
9. Dik WA, Pike-Overzet K, Weerkamp F, de Ridder D, de Haas EF, Baert MR et al. New insights on human T cell development by quantitative T cell receptor gene rearrangement studies and gene expression profiling. J Exp Med 2005 ;201: 1715-23.
10. Eberl G, Littman DR. Thymic origin of intestinal alphabeta T cells revealed by fate mapping of ROR gammat+ cells. Science 2004;305:248-51.
11. von Boehmer H. Selection of the T-cell repertoire: receptor-controlled checkpoints in T-cell development. Adv Immunol 2004;84:201-38.
12. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science 1999;284(5415):770-6.
13. Rebay I, Fleming RJ, Fehon RG, Cherbas L, Cherbas P, Artavanis-Tsakonas S. Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor. Cell 1991;67:687-99.
14. de Celis JF, Barrio R, del Arco A, Garcia-Bellido A. Genetic and molecular characterization of a Notch mutation in its Delta- and Serrate-binding domain in Drosophila. Proc Natl Acad Sci USA 1993;90:4037-41.
15. Weinmaster G. The ins and outs of notch signalling. Mol Cell Neurosci 1997;9:91-102.
16. Matsuno K, Diederich RJ, Go MJ, Blaumueller CM, Artavanis-Tsakonas S. Deltex acts as a positive regulator of Notch signalling through interactions with the Notch ankyrin repeats. Development 1995;121:2633-44.
17. Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD. MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nat Genet 2000;26:484-9.
18. Mumm JS, Kopan R. Notch signalling: from the outside in. Dev Biol 2000;228:151-65.
19. Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 2006;7:678-89.
20. Fiuza UM, Arias AM. Cell and molecular biology of Notch. J Endocrinol 2007; 194:459-74.
21. Jarriault S, Le Bail 0, Hirsinger E, Pourquie 0, Logeat F, Strong CF, et al. Delta-1 activation of notch-1 signalling results in HES-1 transactivation. Mol Cell Biol 1998;18:7423-31.
22. Kuroda K, Tani S, Tamura K, Minoguchi S, Kurooka H, Honjo T. Delta-induced Notch signalling mediated by RBP-J inhibits MyoD expression and myogenesis. J Biol Chem 1999;274:7238-44.
23. Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A. Signalling downstream of activated mammalian Notch [see comments]. Nature 1995;377:355-8.
24. Iso T, Sartorelli V, Chung G, Shichinohe T, Kedes L, Hamamori Y. HERP, a new primary target of Notch regulated by ligandbinding. Mol Cell Biol 2001;21:6071-9.
25. Chang D, Valdez P, Ho T, Robey E. MHC recognition in thymic development: Distinct, parallel pathways for survival and lineage commitment. J Immunol 2000;165:6710-5.
26. Deftos ML, Huang E, Ojala EW, Forbush KA, Bevan MJ. Notch1 signaling promotes the maturation of CD4 and CD8 SP thymocytes. Immunity 2000;13:73-84.
27. Deftos ML, He YW, Ojala EW, Bevan MJ. Correlating Notch signaling with thymocyte maturation. Immunity 1998;9:777-86.
28. Campese AF, Garbe AI, Zhang F, Grassi F, Screpanti I, von Boehmer H. Notch1-dependent lymphomagenesis is assisted by but does not essentially require pre-TCR signaling. Blood 2006;108:305-10.
29. Pirot P, Grunsven LA, Marine JC, Huylebroeck D, Bellefroid EJ. Direct regulation of the Nrarp gene promoter by the Notch signaling pathway. Biochem Biophys Res Comm 2004;322:526-34.
30. Maillard I, Tu L, Sambandam A, Yashiro-Ohtani Y, Millholland J, Keeshan K, et al. The requirement for Notch signaling at the b-selection checkpoint in vivo is absolute and independent of the pre-T cell receptor. J Exp Med 2006;203:2239-45.
31. Amsen D, Blander JM, Lee GR, Tanigaki K, Honjo T, Flavell RA. Instruction of distinct CD4 T helper cell fates by different Notch ligands on antigen-presenting cells. Cell 2004; 117:515-26.
32. Tanaka S, Tsukada J, Suzuki W, Hayashi K, Tanigaki K, Tsuji M, et al. The Interleukin-4 enhancer CNS-2 isregulated by Notch signals and controls initial expression inNKT cells and memory-type CD4 T cells. Immunity 2006;24:689-701.
33. Minter LM, Turley DM, Das P, Shin HM, Joshi I, Lawlor RG, et al. Inhibitors ofgamma-secretase block in vivo and in vitro T helper type 1polarization by preventing Notch upregulation of Tbx21. Nat Immunol 2005;6:680-688.
34. Amsen D, Antov A, Jankovic D, Sher A, Radtke F, Souabni A, et al. Direct regulationof Gata3 expression determines the T helper differentiation potential of Notch. Immunity 2007;27:89-99.
35. Fang TC, Yashiro-Ohtani Y, del Bianco C, Knoblock DM, Blacklow SC, Pear WS. Notch directly regulates Gata3 expression during T helper 2 cell differentiation. Immunity 2007;27:100-110.
36. Ordentlich P, Lin A, Shen CP, Blaumueller C, Matsuno K, Artavanis-Tsakonas S, Notch inhibition of E47 supports the existence of a novel signalling pathway. Mol Cell Biol 1998;18:2230-9.
37. Kojika S, Griffin JD. Notch receptors and hematopoiesis. Exp Hematol 2001;29:1041-52.
38. Washburn T, Schweighoffer E, Gridley T, Chang D, Fowlkes BJ, Cado D, et al. Notch activity influences the alphabeta versus gammadelta T cell lineage decision. Cell 1997;88:833-43.
39. Hasserjian RP, Aster JC, Davi F, Weinberg DS, Sklar J. Modulated expression of notch1 during thymocyte development. Blood 1996;88:970-6.
40. Anderson G, Pongracz J, Parnell S, Jenkinson EJ. Notch ligand-bearing thymic epithelial cells initiate and sustain Notch signaling in thymocytes independently of T cell receptor signalling. Eur J Immunol 2001 ;31:3349-54.
41. Pear W S, Aster J C, Scott M L, Hasserjian R P, Soffer B, Sklar J, et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med 1996; 183:2283-2291.
42. Gothert JR, Brake RL, Smeets M, Duhrsen U, Begley CG, Izon DJ. NOTCH1 pathway activation is an early hallmark of SCL T leukemogenesis. Blood 2007;110(10):3753-62.
43. Wang SF, Aoki M, Nakashima Y, Shinozuka Y, Tanaka H, Taniwaki M, et al. Development of Notch-dependent T-cell leukemia by deregulated Rap1 signaling. Blood 2008;111(5):2878-86.
44. Kindler T, Cornejo MG, Scholl C, Liu J, Leeman DS, Haydu JE, et al. K-RasG12D-induced T-cell lymphoblastic lymphoma/leukemias harbor Notch1 mutations and are sensitive to gamma-secretase inhibitors. Blood 2008;112(8):3373-82.
45. Radtke F, Wilson A, Mancini SJ, MacDonald HR. Notch regulation of lymphocyte development and function. Nat Immunol 2004;5:247-253.
46. Radtke F, Wilson A, MacDonald HR. Notch signaling in hematopoiesis and lymphopoiesis: lessons from Drosophila. BioEssays 2005;27:1117-1128.
47. Radtke F, Wilson A, Stark G, Bauer M, van Meerwijk J, MacDonald HR, et al. Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 1999;10:547-558.
48. HozumiK, Negishi N, Suzuki D, Abe N, Sotomaru Y, Tamaoki N, et al. Delta-like 1 is necessary for the generation of marginal zone B cells but not T cells in vivo. Nat Immunol 2004;5:638-644.
49. Schmitt TM, Zuniga-Pflucker JC. T-cell development, doing it in a dish. Immunol Rev 2006;209:95-102.
50. Rampal R, Li AS, Moloney DJ, Georgiou SA, Luther KB, Nita-Lazar A, et al. Lunatic fringe, manic fringe, and radical fringe recognize similar specificity determinants in O-fucosylated epidermal growth factor-like repeats. J Biol Chem 2005;280:42454-42463.
51. Nie L, Perry SS, Zhao Y, Huang J, Kincade PW, Farrar MA, et al. Regulation of lymphocyte development by cell-type-specific interpretation of Notch signals. Mol Cell Biol 2008;28(6):2078-90.
52. Koch U, Yuan JS, Harper JA, Guidos CJ. Fine-tuning Notch1 activation by endocytosis and glycosylation. Semin Immunol 2003;15:99-106.
53. Wolfer A, Wilson A, Nemir M, MacDonald HR, Radtke F. Inactivation of Notch1 impairs VDJbeta rearrangement and allows pre-TCR-independent survival of early alpha beta Lineage Thymocytes. Immunity 2002; 16:869-879.
54. Ge C, Stanley P. The O-fucose glycan in the ligand-binding domain of Notch1 regulates embryogenesis and T cell development. PNAS 2008;105(5):1539-44.
55. Ciofani M, Schmitt TM, Ciofani A, Michie AM, Cuburu N, Aublin A, et al. Obligatory Role for Cooperative Signaling by Pre-TCR and Notch during Thymocyte Differentiation. J Immunol 2004; 172:5230-5239.
56. Onoyama I, Tsunematsu R, Matsumoto A, Kimura T, de Alboran IM, Nakayama K, et al. Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis. J Exp Med 2007;204:2875-2888.
57. Kitamoto T, Takahashi K, Takimoto H, Tomizuka K, Hayasaka M,Tabira T, et al. Functional redundancy of the Notch gene family during mouse embryogenesis: Analysis of Notch gene expression in Notch3-deficient mice. Biochem Biophys Res Comm 2005;331:1154-1162.
58. Vercauteren SM, Sutherland HJ. Constitutively active Notch4 promotes early human hematopoietic progenitor cell maintenance while inhibiting differentiation and causes lymphoid abnormalities in vivo. Blood 2004; 104:2315-2322.
59. Wolfer A, Bakker T, Wilson A, Nicolas M, Ioannidis V, Littman DR, et al. Inactivation of Notch I in immature thymocytes does not perturb CD4 or CD8T cell development. Nature 2001;2:235-241.
60. Plas DR, Thompson CB. Akt-dependent transformation: there is more to growth than just surviving. Oncogene 2005;24:7435-7442.
61. Manning BD, Cantley LC. AKT/PKB Signaling: Navigating Downstream. Cell 2007;129:1261-1274.
62. Toulany M, Baumann M, Rodemann HP. Stimulated PI3K-AKT signaling mediated through ligand or radiation-induced EGFR depends indirectly, but not directly, on constitutive K-Ras activity. Mol Cancer Res 2007;5(8):863-72.
63. Shelton JG, Steelman LS, Abrams SL, White ER, Akula SM, Franklin RA, et al. Conditional EGFR promotes cell cycle progression and prevention of apoptosis in the absence of autocrine cytokines. Cell Cycle 2005;4(6):822-30.
64. Fruman DA. The role of class I phosphoinositide 3-kinase in T-cell function and autoimmunity.Biochem Soc Trans 2007;035:177-180.
65. Andrews S, Stevens LR, Hawkins PT. PI3K class IB pathway. Sci STKE 2007;2007(407):cm2.
66. Fruman DA, Snapper SB, Yballe CM, Davidson L, Yu JY, Alt FW, et al. Impaired B Cell Developmentand Proliferation in Absence of Phosphoinositide 3-Kinase p85. Science 1999;283:393-397.
67. Deane JA, Trifilo MJ, Yballe CM, Choi S, Lane TE, Fruman DA. Enhanced T Cell Proliferation inMice Lacking the p850 Subunit of Phosphoinositide 3-Kinase. J Immunol 2004; 172:6615-6625.
68. Deane JA, Kharas MG, Oak JS, Stiles LN, Luo J, Moore TI, et al. T-cell function is partiallymaintained in the absence of class IA phosphoinositide 3-kinase signaling. Blood 2007; 109:2894-2902.
69. Oak JS, Deane JA, Kharas MG, Luo J, Lane TE, Cantley LC, et al. Sjogren's syndrome-like diseasein mice with T cells lacking class 1A phosphoinositide-3-kinase. Proc Nat Acad Sci USA 2006; 103:16882-16887.
70. Sasaki T, Irie-Sasaki J, Jones RG, Oliveira-dos-Santos AJ, Stanford WL, Bolon B, et al. Function of PI3K in Thymocyte Development, T Cell Activation, and Neutrophil Migration. Science 2000;287:1040-1046.
71. Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, et al. Impaired B and T Cell Antigen Receptor Signaling in p110delta PI 3-Kinase Mutant Mice. Science 2002;297:1031-1034.
72. Webb LMC, Vigorito E, Wymann MP, Hirsch E, Turner M. Cutting Edge: T Cell DevelopmentRequires the Combined Activities of the p110γ and p110δ Catalytic Isoforms of Phosphatidylinositol3-Kinase. J Immunol 2005;175:2783-2787.
73. Swat W, Montgrain V, Doggett TA, Douangpanya J, Puri K, Vermi W, et al. Essential role ofPI3Kδ and PI3Kγ in thymocyte survival. Blood 2006;107:2415-2422.
74. Hagenbeek TJ, Naspetti M, Malergue F, Garcon F, Nunes JA, Cleutjens KBJM, et al. The Loss ofPTEN Allows TCR αβ Lineage Thymocytes to Bypass IL-7 and Pre-TCR-mediated Signaling. J ExpMed 2004;200:883-894.
75. Zinda MJ, Johnson MA, Paul JD, Horn C, Konicek BW, Lu ZH, et al. AKT-1, -2, and -3 are expressed in both normal and tumor tissues of the lung, breast, prostate, and colon. Clin Cancer Res 2001;7(8):2475-9.
76. Juntilla MM, Wofford JA, Bimbaum MJ, Rathmell JC, Koretzky GA. Akt1 and Akt2 are requiredfor αβ thymocyte survival and differentiation. Proc Nat Acad Sci USA 2007;104:12105-12110.
77. Hinton HJ, Clarke RG, Cantrell DA. Antigen receptor regulation of phosphoinositide-dependent kinase 1 pathways during thymocyte development. FEBS Lett 2006;580: 5845-5850.
78. Mao C, Tili EG, Dose M, Haks MC, Bear SE, Maroulakou I, et al. Unequal contribution of akt isoforms in the doublenegativeto double-positive thymocyte transition. J Immunol 2007;178:5443-5453
79. Kelly AP, Finlay DK, Hinton HJ, Clarke RG, Fiorini E, Radtke F, et al. Notch-induced T cell development requires phosphoinositide-dependent kinase 1 EMBO J 2007;26(14):3441-5
80. Hinton HJ, Alessi DR, Cantrell DA. The serine kinase phosphoinositide-dependent kinase 1 (PDK1) regulates T cell development. Nat Immunol 2004;5:539-545.
81. Jones RG, Parsons M, Bonnard M, Chan VSF, Yeh W-C, Woodgett JR, et al. Protein Kinase BRegulates T Lymphocyte Survival, Nuclear Factor k Activation, and Bcl-XL Levels In Vivo. J ExpMed 2000;191:1721-1734.
82. Ciofani M, Zuniga-Pflucker JC. Notch promotes survival of pre-T cells at the β-selection checkpoint by regulating cellular metabolism. Nat Immunol 2005;6:881-888.
83. Zeiser R, Negrin RS. Interleukin-2 receptor downstream events in regulatory T cells: implications for the choice of immunosuppressive drug therapy. Cell Cycle 2008;7(4):458-62.
84. Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci U S A 2008;105(22):7797-802.
85. Aster JC, Xu L, Karnell FG, Patriub V, Pui JC, Pear WS. Essential roles for ankyrin repeat and transactivation domains in induction of T-cell leukemia by notch1. Mol Cell Biol 2000;20:7505-7515.
86. Lee SY, Kumano K, Masuda S, Hangaishi A, Takita J, Nakazaki K et al. Mutations of the Notch1 gene in T-cell acute lymphoblastic leukemia: analysis in adults and children. Leukemia 2005; 19:1841 -1843.
87. Mansour MR, Linch DC, Foroni L, Goldstone AH, Gale RE. High incidence of Notch-1 mutations in adult patients with T-cell acute lymphoblastic leukemia. Leukemia 2006;20:537-539.
88. O'Neil J, Calvo J, McKenna K, Krishnamoorthy V, Aster JC, Bassing CH, et al. Activating Notch1 mutations in mouse models of T-ALL. Blood 2006; 107(2):781-5.
89. Weng AP, Aster JC. Multiple niches for Notch in cancer: context is everything. Curr Opin Genet Dev 2004;14:48-54.
90. Leong KG, Karsan A. Recent insights into the role of Notch signaling in tumorigenesis. Blood 2006; 107:2223-2233.
91. Bellavia D, Campese AF, Checquolo S, Balestri A, Biondi A, Cazzaniga G, et al. Combined expression of pTalpha and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis. Proc Natl Acad Sci U S A 2002;99:3788-3793.
92. Felli MP, Vacca A, Calce A, Bellavia D, Campese AF, Grillo R, et al. PKC theta mediates pre-TCR signaling and contributes to Notch3-induced T-cell leukemia. Oncogene. 2005;24:992-1000.
93. Sade H, Krishna S, Sarin A. The anti-apoptotic effect of Notch-1 requires p561ck-dependent, Akt/PKB-mediated signaling in T cells. J Biol Chem 2004;279:2937-2944.
94. Guo D, Ye J, Dai J, Li L, Chen F, Ma D, et al. Notch-1 regulates Akt signaling pathway and the expression of cell cycle regulatory proteins cyclin D1, CDK2 and p21 in T-ALL cell lines. Leuk Res 2009;33(5):678-85.
95. Talora C, Campese AF, Bellavia D, Pascucci M, Checquolo S, Groppioni M, et al. Pre-TCR-triggered ERK signalling-dependent downregulation of E2A activity in Notch3-induced T-cell lymphoma. EMBO Rep 2003;4:1067-1072.
96.Mungamuri SK,Yang X,Thor AD,Somasundaram K.Survival signaling by Notch1:mammalian target of rapamycin(mTOR)-dependent inhibition of p53.Cancer Res 2006;66(9):4715-24.
97.Chan SM,Weng AP,Tibshirani R,Aster JC,Utz PJ.Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia.Blood 2007;110(1):278-86.
98.Bellavia D,Campese AF,Alesse E,Vacca A,Felli MP,Balestri A,et al.Constitutive activation of NF-kappaB and T-cell leukemia/lymphoma in Notch3transgenic mice.EMBO J 2000;19:3337-3348.
99.Palomero T,Lim WK,Odom DT,Sulis ML,Real PJ,Margolin A,et al.NOTCH1 directlyregulates c-MYC and activates a feed-forward-loop transcriptional networkpromoting leukemic cell growth.Proc.Natl.Acad.Sci.USA 2006;103:18261-66
100.Lin YW,Nichols RA,Letterio JJ,Aplan PD.Notch1 mutations are important for leukemic transformation in murine models of precursor-T leukemia/lymphoma.Blood 2006;107:2540-3.
101.Zhu YM,Zhao WL,Fu JF,Shi JY,Pan Q,Hu J,et al.NOTCH1 mutations in T-cell acute lymphoblastic leukemia:prognostic significance and implication in multifactorial leukemogenesis.Clin Cancer Res 2006;12(10):3043-9.
102.Mansour MR,Duke V,Foroni L,Patel B,Allen CG,Ancliff PJ,et al.Notch-1mutations are secondary events in some patients with T-cell acute lymphoblastic leukemia.Clin Cancer Res 2007;13(23):6964-9.
103.Cantley LC.The phosphoinositide 3-kinasepathway.Science 2002;296:1655-7
104.Vivanco I,Sawyers CL.Thephosphatidylinositol 3-kinase AKTpathway in human cancer.Nat Rev Cancer 2002;2:489-501.
105.Fry MJ.Phosphoinositide 3-kinasesignalling in breast cancer:how big a role might it play? Breast Cancer Res 2001;3:304-12.
106.Lin X,B(o|¨)hle AS,Dohrmann P,Leuschner I,Schulz A,Kremer B,et al.Overexpression of phosphatidylinositol3-kinase in human lung cancer.Langenbecks Arch Surg 2001;386:293-301.
107.Krasilnikov M, Adler V, Fuchs SY, Dong Z, Haimovitz-Friedman A, Herlyn M, et al. Contribution of phosphatidylinositol3-kinase to radiation resistance in humanmelanoma cells. Mol Carcinog 1999;24:64-9.
108.Martinez-Lorenzo MJ, Anel A, Monleon I, Sierra JJ, Pineiro A, Naval J, et al. Tyrosine phosphorylation of the p85 subunit of phosphatidylinositol3-kinase correlates with high proliferation rates in sublines derived from the Jurkat leukemia. Int J Biochem Cell Biol 2000;32:435-45.
109.Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304:554.
110.Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 2007;448: 39-44.
111. DeGraffenried LA, Fulcher L, Friedrichs WE, Grunwald V, Ray RB, Hidalgo M. Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3kinase/Akt pathway. Ann Oncol 2004;15:1510-6.
112.Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell 2005;8:179-83.
113.Huang HP, Shih YW, Chang YC, Hung CN, Wang CJ. Chemoinhibitory effect of mulberry anthocyanins on melanoma metastasis involved in the Ras/PI3K pathway. J Agric Food Chem 2008;56(19):9286-93.
114.Harir N, Boudot C, Friedbichler K, Sonneck K, Kondo R, Martin-Lanneree S, et al. Oncogenic Kit controls neoplastic mast cell growth through a Stat5/PI3-kinase signaling cascade. Blood 2008;112(6):2463-73.
115.McCubrey JA, Steelman LS, Abrams SL, Lee JT, Chang F, Bertrand FE, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul 2006;46:249-79.
116.Hildebrandt MA, Yang H, Hung MC, Izzo JG, Huang M, Lin J, et al. Genetic variations in the PI3K/PTEN/AKT/mTOR pathway are associated with clinical outcomes in esophageal cancer patients treated with chemoradiotherapy. J Clin Oncol 2009;27(6):857-71.
117.Opitz I, Soltermann A, Abaecherli M, Hinterberger M, Probst-Hensch N, Stahel R, et al. PTEN expression is a strong predictor of survival in mesothelioma patients. Eur J Cardiothorac Surg 2008;33(3):502-6.
118.Zhou L, Huang Y, Li J, Wang Z. The mTOR pathway is associated with the poor prognosis of human hepatocellular carcinoma. Med Oncol 2009.
119.Wu Z, Gioeli D, Conaway M, Weber MJ, Theodorescu D. Restoration of PTEN expression alters the sensitivity of prostate cancer cells to EGFR inhibitors. Prostate 2008;68(9):935-44.
120.Huang WC, Hung MC. Induction of akt activity by chemotherapy confers acquired resistance. J Formos Med Assoc. 2009; 108(3): 180-94.
121.Chen KF, Yeh PY, Hsu C, Hsu CH, Lu YS, Hsieh HP, et al. Bortezomib overcomes TRAIL resistance in hepatocellular carcinoma cells in part through the inhibition of PDK/Akt pathway. J Biol Chem 2009.
122.Cullion K, Draheim KM, Hermance N, Tammam J, Sharma VM, Ware C, et al. Targeting the Notch1 and mTOR pathways in a mouse T-ALL model. Blood 2009.
123.Suzuki A, de la Pompa JL, Stambolic V, Elia AJ, Sasaki T, del Barco Barrantes I, et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr. Biol. Curr Biol 1998;8(21):1169-78.
124.Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM, et al. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci U S A 1999;96(4): 1563-8.
125.Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP. Pten is essential for embryonic development and tumour suppression. Nat Genet 1998;19(4):348-55.
126.Suzuki A, Yamaguchi MT, Ohteki T, Sasaki T, Kaisho T, Kimura Y, et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity 2001;14(5):523-34.
127.Silva A, Yunes JA, Cardoso BA, Martins LR, Jotta PY, Abecasis M, et al. PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability. J Clin Invest 2008; 118(11):3762-74.
128.Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006;441(7092):475-82.
129.Chang H, Qi XY, Claudio J, Zhuang L, Patterson B, Stewart AK. Analysis of PTEN deletions and mutations in multiple myeloma. Leuk Res 2006;30(3):262-5.
130.Aggerholm A, Gr(?)nbaek K, Guldberg P, Hokland P. Mutational analysis of the tumour suppressor gene MMAC1/PTEN in malignant myeloid disorders. Eur J Haematol 2000;65(2): 109-13.
131.Sakai A, Thieblemont C, Wellmann A, Jaffe ES, Raffeld M. PTEN gene alterations in lymphoid neoplasms. Blood 1998;92(9):3410-5.
132.Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006;7:606-619.
133.Trotman LC, Pandolfi PP. PTEN and p53: who will get the upper hand? Cancer Cell 2003;3:97-99.
134.Sulis ML, Parsons R. PTEN: from pathology to biology. Trends Cell Biol 2003;13(9):478-83.
135.Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 1998;273(22): 13375-8.
136.Hoemann CD, Beaulieu N, Girard L, Rebai N, Jolicoeur P. Two distinct Notch1 mutant alleles are involved in the induction of T-cell leukemia in c-myc transgenic mice. Mol Cell Biol 2000;20(11):3831-42.
137.Feldman BJ, Hampton T, Cleary ML. A carboxy-terminal deletion mutant of Notch1 accelerates lymphoid oncogenesis in E2A-PBX1 transgenic mice. Blood 2000;96(5):1906-13.
138.Weng AP, Nam Y, Wolfe MS, Pear WS, Griffin JD, Blacklow SC, et al. Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Mol Cell Biol 2003;23(2):655-64.
139.Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C, Del Bianco C, et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 2006;20:2096-109.
140.Sharma VM, Calvo JA, Draheim KM, Cunningham LA, Hermance N, Beverly L, et al. Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc. Mol. Cell. Biol 2006;26:8022-31.
141.Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995;378:785-789.
142.Espinosa L, Ingles-Esteve J, Aguilera C, Bigas A. Phosphorylation by glycogen synthase kinase-3 beta down-regulates Notch activity, a link for Notch and Wnt pathways. J Biol Chem 2003;278(34):32227-32235.
143.Foltz DR, Santiago MC, Berechid BE, Nye JS. Glycogen synthase kinase-3beta modulates notch signaling and stability. Curr Biol 2002;12(12):1006-1011.
144.Jin YH, Kim H, Oh M, Ki H, Kim K. Regulation of Notch1 NICD and Hes1 expressions by GSK-3alpha beta. Mol Cells 2009;27(1):15-9.
145.Calzavara E, Chiaramonte R, Cesana D, Basile A, Sherbet GV, Comi P. Reciprocal regulation of Notch and PI3K/Akt signalling in T-ALL cells in vitro. J. Cell. Biochem 2008;103:1405-1412.
146.Bedogni B, Warneke JA, Nickoloff BJ, Giaccia AJ, Powell MB. Notch1 is an effector of Akt and hypoxia in melanoma development. J Clin Invest 2008;118(11):3660-70.
147.Breit S, Stanulla M, Flohr T, Schrappe M, Ludwig WD, Tolle G, et al. Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia. Blood 2006;108:1151-7.
148.Lones MA, Heerema NA, Le Beau MM, Sposto R, Perkins SL, Kadin ME, et al. Chromosome abnormalities in advanced stage lymphoblastic lymphoma of children and adolescents: a report from CCG-E08. Cancer Genet Cytogenet 2007;172:1-11.
149.van Grotel M, Meijerink JP, van Wering ER, Langerak AW, Beverloo HB, Buijs-Gladdines JG, et al. Prognostic significance of molecular-cytogenetic abnormalities in pediatric T-ALL is not explained by immunophenotypic differences. Leukemia 2008;22:124-31.
150.Real PJ, Tosello V, Palomero T, Castillo M, Hernando E, de Stanchina E, et al. Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat Med 2009;15(1):50-8.
[1] De Keersmaecker K, Marynen P, Cools J. Genetic insights in the pathogenesis of T-cell acute lymphoblastic leukemia. Haematologica 2005;90:1116-27.
[2] Graux C, Cools J, Michaux L, Vandenberghe P, Hagemeijer A. Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: from thymocyte to lymphoblast. Leukemia 2006;20:1496-510.
[3] Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004;306:269-71.
[4] Zhu YM, Zhao WL, Fu JF, et al. NOTCH1 mutations in T-cell acute lymphoblastic leukemia: prognostic significance and implication in ultifactorial leukemogenesis. Clin Cancer Res 2006;12:3043-9.
[5] Ellisen LW, Bird J, West DC, et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 1991;66:649-61.
[6] Kogoshi H, Sato T, Koyama T, Nara N, Tohda S. Gamma-secretase inhibitors suppress the growth of leukemia and lymphoma cells. Oncol Rep 2007;18:77-80.
[7] Palomero T, Sulis ML, Cortina M, et al. Mutational loss of PTEN induces resistance to NOTCH 1 inhibition in T-cell leukemia. Nat Med 2007;13:1203-10.
[8] Palomero T, Lim WK, Odom DT, et al. NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci U S A 2006; 103:18261-6.
[9] Sharma VM, Calvo JA, Draheim KM, et al. Notch1 Contributes to Mouse T-Cell Leukemia by Directly Inducing the Expression of c-myc. Mol Cell Biol 2006;26:8022-31.
[10]Iso T, Kedes L, Hamamori Y. HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol 2003;194:237-55.
[11]Kageyama R, Ohtsuka T, Hatakeyama J, Ohsawa R. Roles of bHLH genes in neural stem cell differentiation. Exp. Cell Res 2005;306:343-8.
[12]Weng AP, Millholland JM, Yashiro-Ohtani Y, et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 2006;20:2096-109.
[13]Katoh M, Katoh M. Notch signaling in gastrointestinal tract. Int J Oncol 2007; 30:247-51.
[14]Pissarnitski D. Advances in gamma-secretase modulation. Curr Opin Drug Discov Devel 2007; 10:392-402.
[15]Palomero T, Barnes KC, Real PJ, et al. CUTLL1, a novel human T-cell lymphoma cell line with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to gamma-secretase inhibitors. Leukemia 2006;20:1279-87.
[16]Moussa O, Riker JM, Klein J, Fraig M, Halushka PV, Watson DK. Inhibition of thromboxane synthase activity modulates bladder cancer cell responses to chemotherapeutic agents. Oncogene 2008;27:55-62.
[17]Sherr CJ. G1 phase progression: cycling on cue. Cell 1994;79:551-5.
[18]Dohda T, Maljukova A, Liu L, et al. Notch signaling induces SKP2 expression and promotes reduction of p27Kip1 in T-cell acute lymphoblastic leukemia cell lines. Exp Cell Res. 2007; 313: 3141-3152.
[19] Wang Z, Zhang Y, Li Y, Banerjee S, Liao J, Sarkar FH. Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells. Mol. Cancer Ther 2006;5:483-93.
[20]Ronchini C, Capobianco AJ. Induction of cyclin D1 transcription and CDK2 activity by Notch(ic): implication for cell cycle disruption in transformation by Notch(ic). Mol Cell Biol 2001;21:5925-34.
[21] Li DM, Sun H. PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. Proc Natl Acad Sci U S A 1998;95:15406-11.
[22] Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001 ;411:355-65.
[23]Georgakis GV, Li Y, Rassidakis GZ, Medeiros LJ, Mills GB, Younes A. Inhibition of the phosphatidylinositol-3 kinase/Akt promotes Gl cell cycle arrest and apoptosis in Hodgkin lymphoma. Br J Haematol 2006; 132:503-11.
[24]Mukherji A, Janbandhu VC, Kumar V. GSK-3beta-dependent destabilization of cyclin D1 mediates replicational stress-induced arrest of cell cycle. FEBS Lett 2008;582:1111-6.
[25] He YY, Council SE, Feng L, Chignell CF. UVA-induced cell cycle progression is mediated by a disintegrin and metalloprotease/epidermal growth factor receptor/AKT/Cyclin D1 pathways in keratinocytes. Cancer Res 2008;68:3752-8.
[26]Ikezoe T, Nishioka C, Bandobashi K, et al. Longitudinal inhibition of PI3K/Akt/mTOR signaling by LY294002 and rapamycin induces growth arrest of adult T-cell leukemia cells. Leuk Res 2007;31:673-82.
[27]O'Gorman DM, McKenna SL, McGahon AJ, Cotter TG. Inhibition of PI3-kinase sensitises HL60 human leukaemia cells to both chemotherapeutic drug- and Fas-induced apoptosis by a JNK independent pathway. Leuk Res 2001;25:801-11.
[28] Gutierrez A, Look AT. NOTCH and PI3K-AKT pathways intertwined. Cancer Cell 2007;12:411-3.
[29]Nair P, Somasundaram K, Krishna S. Activated Notch1 inhibits p5 3-induced apoptosis and sustains transformation by human papillomavirus type 16 E6 and E7 oncogenes through a PI3K-PKB/Akt-dependent pathway. J Virol 2003;77:7106-12.
[30]Sade H, Krishna S, Sarin A. The anti-apoptotic effect of Notch-1 requires p561ck-dependent, Akt/PKB-mediated signaling in T cells. J Biol Chem 2004;279:2937-44.
[31]Nefedova Y, Sullivan DM, Bolick SC, Dalton WS, Gabrilovich DI. Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy. Blood 2008; 111:2220-9.
[32]Calzavara E, Chiaramonte R, Cesana D, Basile A, Sherbet GV, Comi P. Reciprocal regulation of Notch and PI3K/Akt signalling in T-ALL cells In Vitro. J Cell Biochem 2008; 103:1405-12.
[33]Breit S, Stanulla M, Flohr T, et al. Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia. Blood 2006; 108:1151-7.
[34]Lones MA, Heerema NA, Le Beau MM, et al. Chromosome abnormalities in advanced stage lymphoblastic lymphoma of children and adolescents: a report from CCG-E08. Cancer Genet Cytogenet 2007;172:1-11.
[35]van Grotel M, Meijerink JP, van Wering ER, et al. Prognostic significance of molecular-cytogenetic abnormalities in pediatric T-ALL is not explained by immunophenotypic differences. Leukemia 2008 ;22:124-31.
1. Liang R, Huang GS, Wang Z, Chen XQ, Bai QX, Zhang YQ, et al. Effects of human bone marrow stromal cell line (HFCL) on the proliferation, differentiation and apoptosis of acute myeloid leukemia cell lines U937, HL-60 and HL-60/VCR. Int J Hematol 2008;87:152-66.
2. Nefedova Y, Cheng P, Alsina M, Dalton WS, Gabrilovich DI. Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Blood 2004;103:3503-10.
3. Rothenberg EV. Negotiation of the T lineage fate decision by transcription-factor interplay and microenvironmental signals. Immunity 2007;26:690-702.
4. Fischer A, Gessler M. Delta-Notch-and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors. Nucleic Acids Res 2007;35:4583-96.
5. Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 1991;66:649-61.
6. Weng AP, Nam Y, Wolfe MS, Pear WS, Griffin JD, Blacklow SC, et al. Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Mol Cell Biol 2003;23:655-64.
7. Weng AP, Ferrando AA, Lee W, Morris JP 4th, Silverman LB, Sanchez-Irizarry C, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004;306:269-71.
8. Jang J, Choi YI, Choi J, Lee KY, Chung H, Jeon SH, et al. Notch1 confers thymocytes a resistance to GC-induced apoptosis through Deltexl by blocking the recruitment of p300 to the SRG3 promoter. Cell Death Differ 2006;13:1495-505.
9. Sade H, Krishna S, Sarin A. The anti-apoptotic effect of Notch-1 requires p56~(lck)-dependent, Akt/PKB-mediated signaling in T cells. J Biol Chem 2004;279:2937-44.
10. Mungamuri SK, Yang X, Thor AD, Somasundaram K. Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53. Cancer Res 2006;66:4715-24.
11. Nefedova Y, Sullivan DM, Bolick SC, Dalton WS, Gabrilovich DI. Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy. Blood 2008; 111:2220-29.
12. Kogoshi H, Sato T, Koyama T, Nara N, Tohda S. Gamma-secretase inhibitors suppress the growth of leukemia and lymphoma cells. Oncol Rep 2007; 18:77-80.
13. Katoh M, Katoh M. Notch signaling in gastrointestinal tract. Int J Oncol 2007;3:247-51.
14. Pissarnitski D. Advances in gamma-secretase modulation. Curr Opin Drug Discov Devel 2007; 10:392-402.
15. Lagneaux L, Delforge A, Bron D, De Bruyn C, Stryckmans P. Chronic lymphocytic leukemic B cells but not normal B cells are rescued from apoptosis by contact with normal bone marrow stromal cells. Blood 1998;91:2387-96.
16. Dankbar B, Padro T, Leo R, Feldmann B, Kropff M, Mesters RM, et al. Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma. Blood 2000;95:2630-6.
17. Tabe Y, Jin L, Tsutsumi-Ishii Y, Xu Y, McQueen T, Priebe W, et al. Activation of integrin-linked kinase is a critical prosurvival pathway induced in leukemic cells by bone marrow-derived stromal cells. Cancer Res 2007;67:684-94.
18. Winter SS, Sweatman J, Shuster JJ, Link MP, Amylon MD, Pullen J, et al. Bone marrow stroma-supported culture of T-lineage acute lymphoblastic leukemic cells predicts treatment outcome in children: a Pediatric Oncology Group study. Leukemia 2002;16:1121-6.
19. Scupoli MT, Perbellini O, Krampera M, Vinante F, Cioffi F, Pizzolo G. Interleukin 7 requirement for survival of T-cell acute lymphoblastic leukemia and human thymocytes on bone marrow stroma. Haematologica 2007;92:264-6.
20. Rutz S, Mordmuller B, Sakano S, Scheffold A. Notch ligands Delta-likel, Delta-like4 and Jagged1 differentially regulate activation of peripheral T helper cells. Eur J Immunol 2005; 35:2443-51.
21. Bash J, Zong WX, Banga S, Rivera A, Ballard DW, Ron Y, et al. Rel/NF-kappaB can trigger the Notch signaling pathway by inducing the expression of Jagged1, a ligand for Notch receptors. EMBO J 1999;18:2803-l 1.
22. Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M, et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 2007;13:1203-10.
23. Rangarajan A, Syal R, Selvarajah S, Chakrabarti O, Sarin A, Krishna S. Activated Notch1 signaling cooperates with papillomavirus oncogenes in transformation and generates resistance to apoptosis on matrix withdrawal through PKB/Akt. Virology 2001;286:23-30.
24. Nair P, Somasundaram K, Krishna S. Activated Notch1 inhibits p53-induced apoptosis and sustains transformation by human papillomavirus type 16 E6 and E7 oncogenes through a PI3K-PKB/Akt-dependent pathway. J Virol 2003;77:7106-12.
25. Bheeshmachar G, Purushotaman D, Sade H, Gunasekharan V, Rangarajan A, Sarin A. Evidence for a role for notch signaling in the cytokine-dependent survival of activated T cells. J Immunol 2006;177:5041-50.
26. Foltz DR, Santiago MC, Berechid BE, Nye JS. Glycogen synthase kinase-3beta modulates notch signaling and stability. Curr Biol 2002;12:1006-11.
2.Dear R,Wilcken N,Shannon J,et al.Beyond chemotherapy—demystifying the new 'targeted' cancer treatments.Aust Fam Physician.2004;37(1-2):45-49.
3.D'Addario G,Rauch D,Stupp R,et al.Multicenter phase Ⅱ trial of gefitinib first-line therapy followed by chemotherapy in advanced non-small-cell lung cancer(NSCLC):SAKK protocol 19/03.Ann Oncol.2008;19(4):739-45.
4.Gajraj E,Chung H,Longson C,et al.Rituximab for follicular non-Hodgkin lymphoma.Lancet Oncol.2008;9(4):320-1.
5.Egan SE,St-Pierre B,Leow CC.Notch receptors,partners and regulators:from conserved domains to powerful functions.Curr Top Microbiol Immunol.1998;228:273-324.
6.Artavanis-Tsakonas S,Rand MD,Lake RJ.Notch signaling:cell fate control and signal integration in development.Science.1999;284:770-776.
7.Callahan R,Egan SE.Notch signaling in mammary development and oncogenesis.Mammary Gland Biol Neoplasia.2004;9:145-163.
8.Dontu G,AL-Hajj M,Abdallah WM,Clarke MF,Wicha MS.Stem cells in normal breast development and breast cancer.Cell Prolif.2003;36 Suppl 1:59-72.
9.Dontu G,Jackson KW,McNicholas E,Kawamura MJ,Abdallah WM,Wicha MS.Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells.Breast Cancer Res.2004;6:R605-615.
10.叶静静,马道新,赵建强,纪春岩.四种Notch配体信号功能活性比较.山东医药.2004;44(7):13-15.
11.Kopan R.Notch:a membrane-bound transcription factor.Cell Sci.2002;115:1095-1097.
12.Lai EC.Keeping a good pathway down:transcriptional repression of Notch pathway target genes by CSL proteins.EMBO Rep.2002;3:840-845.
13. Fortini ME, Artavanis-Taskonas S. The suppressor of hairless protein participates in Notch receptor signaling. Cell. 1994;79:273-282.
14. Honjo T. The shortest path from the surface to the nucleus: RBPJK/Su(H) transcription factor. Genes Cell. 1996;1:1-9.
15. Ellisen LW, Bird J, West DC, et al. TAN 1, the human homolog of the Drosophila notch gone, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell. 1991;66(4): 649-661.
16. Aster JC, Xu L, Karnell FG, Patriub V, Pui JC, Pear WS. Essential roles for ankyrin repeat and transactivation domains in induction of T-cell leukemia by notchl. Mol Cell Biol. 2000;20(20):7505-15
17. Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science. 2004;306:269-71.
18. Zhu YM, Zhao WL, Fu JF, et al. NOTCH1 mutations in T-cell acute lymphoblastic leukemia: prognostic significance and implication in ultifactorial leukemogenesis. Clin Cancer Res. 2006;12:3043-9.
19. Capobianco AJ, Zagouras P, Blaumueller CM, Artavanis-Tsakonas S, Bishop JM. Neoplastic transformation by truncated alleles of human NOTCH1/TAN1 and N0TCH2. Mol Cell Biol. 1997;17(11):6265-73
20. Bellavia D, Campese AF, Checquolo S, et al. Combined expression of pTalpha and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis. Proc Natl Acad Sci U S A. 2002;99(6):3788-93.
21. Lipardi C, Wei Q, Paterson BM. RNAi as random degradeative PCR. SiRNA primers convert mRNA into dsRNAs that are degraded to generate new siRNAs. Cell. 2001;107:297-307.
22. Nishikura K. A Short primer on RNAi. RNA-directed RNA polymerase acts as a key catalyst. Cell. 2001;107:415-418.
23. Caplen NJ, Parrish S, Imani F, et al. Specific inhibition of gene expression by small double-stranded RNAs in invertebrate and vertebrate systems [J]. Proc Natl Acad Sci USA. 2001;98:9742-9747.
24. Wharton KA, Johansen KM, Xu T, et al. Nucleotide sequence from the neurogenic locus notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell. 1985;43(3Pt2):567-581.
25. Lieber T, Kidd S, Alcamo E, et al. Antineurogenic phenotypes induced by truncated Notch proteins indicate a role in signal transduction and may point to a novel function for Notch in nuclei. Genes Dev. 1993;7 (10): 1949-1965.
26. Struhl G, Fitzgerald K, Greenwald I. Intrinsic activity of the Lin 12 and Notch intracellular domains in vivo. Cell. 1993;74 (2):331-345.
27. Logeat F, Bessia C, Brou C, et al. The Notchl receptor is cleaved constitutively by a furin-like convertase. Proc Natl Acad Sci USA. 1998;95 (14):8108-8112.
28. Artavanis Tsakonas S, Matsuno K, Fortini ME. Notch signaling. Science. 1995;268 (5208):225-232.
29. Zagouras P, Stifani S, Blaumueller CM, et al. Alterations in Notch signaling in neoplastic lesions of the human cervix. Proc Natl Acad Sci USA. 1995;92 (14):6414-6418.
30. Leethanakul C, Patel V, Gillespie J, et al. Distinct pattern of expression of differentiation and growth-related genes in squamous cell carcinomas of the head and neck revealed by the use of laser capture micro dissection and cDNA arrays. Oncogene. 2000;19(28):3220-3224.
31. Enlund F, Behboudi A, Andren Y, et al. Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors. Exp Cell Res. 2004;292(1):21-28.
32. Jundt F, Schulze Proebsting KS, Anagnostopoulos I, et al. Jagged1-induced Notch signaling drives proliferation of multiple myeloma cells. Blood. 2004; 103(9):3511-3515.
33. Gray GE, Mann RS, Mitsiadis E, et al. Human ligands of the Notch receptor. Am J Patho1.1999; 154(3):785-794.
34. Zagouras P, Stifani S, Blaumueller CM, et al. Alterations in Notch signaling in neoplastic lesions of the human cervix. Proc Natl Acad Sci U S A. 1995;92(14):6414-6418.
35. Miyamoto Y, Maitra A, Ghosh B, et al. Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell.2003;3(6):565-576.
36. Cuevas IC, Slocum AL, Jun P, et al. Meningioma transcript profiles reveal deregulated Notch signaling pathway. Cancer Res.2005;65(12):5070-5075.
37. Purow BW, Haque RM, Noel MW, et al. Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. Cancer Res. 2005;65(6):2353-2363.
38. Jundt F, Anagnostopoulos I, Forster R, et al. Activated Notchl signaling promotes tumor cell proliferation and survival in Hodgkin and anaplastic large cell lymphoma. Blood. 2002;99(9):3398-3403.
39. Houde C, Li Y, Song L, et al. Overexpression of the NOTCH ligand JAG2 in malignant plasma cells from multiple myeloma patients and cell lines. Blood. 2004;104(12):3697-3704.
40. Jundt F, Probsting KS, Anagnostopoulos I, et al. Jaggedl-induced Notch signaling drives proliferation of multiple myeloma cells. Blood. 2004;103(9):3511-3515.
41. Tohda S, Nara N. Expression of Notchl and Jaggedl proteins in acute myeloid leukemia cells. Leuk Lymphoma. 2001;42(3):467-472.
42. Kogoshi H, Sato T, Koyama T, et al. Gamma-secretase inhibitors suppress the growth of leukemia and lymphoma cells. Oncol Rep. 2007;18(1):77-80.
43. Nefedova Y, Sullivan DM, Bolick SC, et al. Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy. Blood. 2008;111(4):2220-2229.
44. Siemers ER, Dean RA, Friedrich S, et al. Safety, tolerability, and effects on plasma and cerebrospinal fluid amyloid-beta after inhibition of gamma-secretase. Clin Neuropharmacol. 2007;30(6):317-325.
45. Palomero T, Sulis ML, Cortina M, et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med. 2007;13:1203-1210.
46. Palomero T, Lim WK, Odom DT, et al. NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci U S A. 2006;103:18261-18266.
47. Sharma VM, Calvo JA, Draheim KM, et al. Notch1 Contributes to Mouse T-Cell Leukemia by Directly Inducing the Expression of c-myc. Mol Cell Biol. 2006;26:8022-8031.
48. Yan S, Wenner CE. Modulation of CyclinD1 and its signaling components by the phorbol ester TPA and the tyrosine phosphatase inhibitor vanadate. Cell Physiol. 2001; 186:338-349.
49. Kato J. Induction of S phase by G1 regulatory factors. Front Biosci. 1999;4:D787-92.
50. Cook SJ, Balmanno K, Garner A, Millar T, Taverner C, Todd D. Regulation of cell cycle re-entry by growth, survival and stress signalling pathways. Biochem Soc Trans. 2000;28(2):233-240.
51. Park US, Park SK, Lee YI, Park JG, Lee YI. Hepatitis B virus-X protein upregulates the expression of p21waf1/cip1 and prolongs G1-->S transition via a p53-independent pathway in human hepatoma cells. Oncogene. 2000;19(30):3384-3394.
52. Stewart ZA, Pietenpol JA. p53 Signaling and cell cycle checkpoints. Chem Res Toxicol. 2001;14(3):243-263.
53. Mungamuri SK, Yang X, Thor AD, Somasundaram K. Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53. Cancer Res. 2006; 66:4715-4724.
54. Henning K, Heering J, Schwanbeck R, et al. Notch1 activation reduces proliferation in the multipotent hematopoietic progenitor cell line FDCP-mix through a p53-dependent pathway but Notch1 effects on myeloid and erythroid differentiation are independent of p53. Cell Death Differ. 2008;15:398-407.
55. Zhang W, Funk WD, Wright WE, Shay JW, Deisseroth AB. Novel DNA binding of p53 mutants and their role in transcriptional activation. Oncogene. 1993;8(9):2555-9.
56. Cully M, You H, Levine AJ, et al. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer. 2006;6:184-192.
57. Rosen N, She QB. AKT and cancer--is it all mTOR? Cancer Cell. 2006;10:254-256.
58. Urano J, Sato T, Matsuo T, et al. Point mutations in TOR confer Rheb-independent growth in fission yeast and nutrient-independent mammalian TOR signaling in mammalian cells. Proc Natl Acad Sci U S A. 2007;104:3514-3519.
59. Takahashi K, Murakami M, Yamanaka S. Role of the phosphoinositide 3-kinase pathway in mouse embryonic stem (ES) cells. Biochem Soc Trans. 2005;33:1522-1525.
60. Zhang H, Bajraszewski N, Wu E, et al. PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. J Clin Invest. 2007; 117:730-738.
61. Saal LH, Holm K, Maurer M, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005;65:2554-2559.
62. Robertson GP. Functional and therapeutic significance of Akt deregulation in malignant melanoma. Cancer Metastasis Rev. 2005;24:273-285.
63. Gutierrez A, Look AT. NOTCH and PI3K-AKT pathways intertwined. Cancer Cell. 2007;12:411-413.
64. Calzavara E, Chiaramonte R, Cesana D, Basile A, Sherbet GV, Comi P. Reciprocal regulation of Notch and PI3K/Akt signalling in T-ALL cells In Vitro. J Cell Biochem. 2008;103:1405-1412.
65. Palomero T, Sulis ML, Cortina M, et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med. 2007;13:1203-1210.
66. Breit S, Stanulla M, Flohr T, et al. Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia. Blood. 2006;108:1151-1157.
67. Lones MA, Heerema NA, Le Beau MM, et al. Chromosome abnormalities in advanced stage lymphoblastic lymphoma of children and adolescents: a report from CCG-E08. Cancer Genet Cytogenet. 2007; 172:1-11.
68. van Grotel M, Meijerink JP, van Wering ER, et al. Prognostic significance of molecular-cytogenetic abnormalities in pediatric T-ALL is not explained by immunophenotypic differences. Leukemia. 2008;22:124-131.
1. Tavor S, Eisenbach M, Jacob-Hirsch J, et al. The CXCR4 antagonist AMD3100 impairs survival of human AML cells and induces their differentiation. Leukemia. 2008;22(12):2151-2158.
2. Gallay N, Anani L, Lopez A, et al. The role of platelet/endothelial cell adhesion molecule 1 (CD31) and CD38 antigens in marrow microenvironmental retention of acute myelogenous leukemia cells. Cancer Res. 2007;67(18):8624-8632.
3. Lwin T, Hazlehurst LA, Li Z, et al. Bone marrow stromal cells prevent apoptosis of lymphoma cells by upregulation of anti-apoptotic proteins associated with activation of NF-kappaB (RelB/p52) in non-Hodgkin's lymphoma cells. Leukemia. 2007;21(7): 1521-1531.
4. Gibson LF. Survival of B lineage leukemic cells: signals from the bone marrow microenvironment. Leuk Lymphoma. 2002;43(1):19-27.
5. Liang R, Huang GS, Wang Z, et al. Effects of human bone marrow stromal cell line (HFCL) on the proliferation, differentiation and apoptosis of acute myeloid leukemia cell lines U937, HL-60 and HL-60/VCR. Int J Hematol. 2008;87:152-166.
6. Nefedova Y, Cheng P, Alsina M, Dalton WS, Gabrilovich DI. Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Blood. 2004;103:3503-3510.
7. Konopleva M, Konoplev S, Hu W, Zaritskey AY, Afanasiev BV, Andreeff M. Stromal cells prevent apoptosis of AML cells by up-regulation of anti-apoptotic proteins. Leukemia. 2002;16(9):1713-1724.
8. Lagneaux L, Delforge A, Bron D, De Bruyn C, Stryckmans P. Chronic lymphocytic leukemic B cells but not normal B cells are rescued from apoptosis by contact with normal bone marrow stromal cells. Blood. 1998;91(7):2387-2396.
9. Iwamoto S, Mihara K, Downing JR, Pui CH, Campana D. Mesenchymal cells regulate the response of acute lymphoblastic leukemia cells to asparaginase. J Clin Invest. 2007; 117:1049-1057.
10.梁蓉,黄高昇,陈协群,等.骨髓成纤维样基质细胞系对急性髓细胞白血病细胞系增殖与分化影响的研究.中华肿瘤防治杂志.2007;14:1281-1285.
11.Liang R,Huang GS,Wang Z,et al.Effects of human bone marrow stromal cell line(HFCL)on the proliferation,differentiation and apoptosis of acute myeloid leukemia cell lines U937,HL-60 and HL-60/VCR.Int J Hematol.2008;87(2):152-166.
12.Wang LH,Yang XY,Zhang X,Farrar WL.Inhibition of adhesive interaction between multiple myeloma and bone marrow stromal cells by PPARgamma cross talk with NF-kappaB and C/EBP.Blood.2007;110(13):4373-4384.
13.Tabe Y,Jin L,Tsutsumi-Ishii Y,et al.Activation of integrin-linked kinase is a critical prosurvival pathway induced in leukemic cells by bone marrow-derived stromal cells.Cancer Res.2007;67(2):684-694.
14.Kobune M,Chiba H,Kato J,et al.Wnt3/RhoA/ROCK signaling pathway is involved in adhesion-mediated drug resistance of multiple myeloma in an autocrine mechanism.Mol Cancer Ther.2007;6(6):1774-1784.
15.Mahlknecht U,Sch(o|¨)nbein C.Histone deacetylase inhibitor treatment downregulates VLA-4 adhesion in hematopoietic stem cells and acute myeloid leukemia blast cells.Haematologica.2008;93(3):443-446.
16.Schmidmaier R,M(o|¨)rsdorf K,Baumann P,Emmerich B,Meinhardt G.Evidence for cell adhesion-mediated drug resistance of multiple myeloma cells in vivo.Int J Biol Markers.2006;21(4):218-222.
17.Kopan R.Notch:a membrane-bound transcription factor.Cell Sci.2002;115:1095-1097.
18.DeJoussineau C,Soule J,Martin M,AnguilleC,Montcourrier P,AlexandreD.Delta-promoted filopodia mediate long-range lateral inhibition in Drosophila.Nature.2003;426(6966):555-559.
19.Struhl G,Adachi A.Requirements for presenilin-dependent cleavage of notch and other transmembrane proteins.Mol Cell.2000;6(3):625-636.
20.Artavanis-Tsakonas S,Rand MD,Lake RJ.Notch signaling:cell fate control and signal integration in development.Science.1999;284:770-776.
21. Jang J, Choi YI, Choi J, Lee KY, Chung H, Jeon SH, et al. Notch1 confers thymocytes a resistance to GC-induced apoptosis through Deltexl by blocking the recruitment of p300 to the SRG3 promoter. Cell Death Differ. 2006;13:1495-1505.
22. Sade H, Krishna S, Sarin A. The anti-apoptotic effect of Notch-1 requires p56~(lck)-dependent, Akt/PKB-mediated signaling in T cells. J Biol Chem 2004;279:2937-2944.
23. Kogoshi H, Sato T, Koyama T, Nara N, Tohda S. Gamma-secretase inhibitors suppress the growth of leukemia and lymphoma cells. Oncol Rep. 2007;18(1):77-80.
24. Mungamuri SK, Yang X, Thor AD, Somasundaram K. Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53. Cancer Res. 2006; 66(9):4715-4724.
25. Nefedova Y, Sullivan DM, Bolick SC, et al. Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy. Blood. 2008; 111 (4):2220-2229.
26. Rangarajan A, Syal R, Selvarajah S, Chakrabarti 0, Sarin A, Krishna S. Activated Notch1 signaling cooperates with papillomavirus oncogenes in transformation and generates resistance to apoptosis on matrix withdrawal through PKB/Akt. Virology. 2001 ;286:23-30.
27. Nair P, Somasundaram K, Krishna S. Activated Notch1 inhibits p53-induced apoptosis and sustains transformation by human papillomavirus type 16 E6 and E7 oncogenes through a PI3K-PKB/Akt-dependent pathway. J Virol. 2003;77:7106-7112.
28. Bheeshmachar G, Purushotaman D, Sade H, Gunasekharan V, Rangarajan A, Sarin A. Evidence for a role for notch signaling in the cytokine-dependent survival of activated T cells. J Immunol 2006; 177:5041-5050.
29. Gutierrez A, Look AT. NOTCH and PI3K-AKT pathways intertwined. Cancer Cell. 2007;12:411-413.
30. Calzavara E, Chiaramonte R, Cesana D, Basile A, Sherbet GV, Comi P. Reciprocal regulation of Notch and PI3K/Akt signalling in T-ALL cells In Vitro. J Cell Biochem. 2008;103:1405-1412.
31. Maliekal TT, Bajaj J, Giri V, Subramanyam D, Krishna S. The role of Notch signaling in human cervical cancer: implications for solid tumors. Oncogene. 2008;27(38):5110-5114.
32. Liu ZJ, Xiao M, Balint K, et al. Inhibition of endothelial cell proliferation by Notch1 signaling is mediated by repressing MAPK and PI3K/Akt pathways and requires MAML1. FASEB J. 2006;20(7): 1009-1011.
33. Foltz DR, Santiago MC, Berechid BE, Nye JS. Glycogen synthase kinase-3beta modulates notch signaling and stability. Curr Biol. 2002;12:1006-1011.
34. Bedogni B, Warneke JA, Nickoloff BJ, Giaccia AJ, Powell MB. J Clin Invest. Notch1 is an effector of Akt and hypoxia in melanoma development. J Clin Invest. 2008;118(11):3660-3670.
1. Artavanis-Tsakonas S, Matsuno K, Fortini ME. Notch signaling. Science 1995;268:225-32.
2. Greenwald I. LIN-12/Notch signaling: lessons from worms and flies. Genes Dev 1998; 12:1751-62.
3. Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, et al. TAN-1, the human homolog of the Drosophila notch gene isbroken by chromosomal translocations in T lymphoblastic neoplasms. Cell 1991;66:649-61.
4. Weng AP, Ferrando AA, Lee W, Morris JP 4th, Silverman LB, Sanchez-Irizarry C, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004;306:269-71.
5. Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M, et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 2007;13(10):1203-10.
6. O'Neil J, Grim J, Strack P, Rao S, Tibbitts D, Winter C, et al. FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitorsJ Exp Med 2007;204(8): 1813-24.
7. Godfrey DI, Zlotnik A. Control points in early T-cell development. Immunol Today 1993;14:547-53.
8. Weerkamp F, de Haas EF, Naber BA, Comans-Bitter WM, Bogers AJ, van Dongen JJ et al. Age-related changes in the cellular composition of the thymus in children. J Allergy Clin Immunol 2005; 115:834-40.
9. Dik WA, Pike-Overzet K, Weerkamp F, de Ridder D, de Haas EF, Baert MR et al. New insights on human T cell development by quantitative T cell receptor gene rearrangement studies and gene expression profiling. J Exp Med 2005 ;201: 1715-23.
10. Eberl G, Littman DR. Thymic origin of intestinal alphabeta T cells revealed by fate mapping of ROR gammat+ cells. Science 2004;305:248-51.
11. von Boehmer H. Selection of the T-cell repertoire: receptor-controlled checkpoints in T-cell development. Adv Immunol 2004;84:201-38.
12. Artavanis-Tsakonas S, Rand MD, Lake RJ. Notch signaling: cell fate control and signal integration in development. Science 1999;284(5415):770-6.
13. Rebay I, Fleming RJ, Fehon RG, Cherbas L, Cherbas P, Artavanis-Tsakonas S. Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor. Cell 1991;67:687-99.
14. de Celis JF, Barrio R, del Arco A, Garcia-Bellido A. Genetic and molecular characterization of a Notch mutation in its Delta- and Serrate-binding domain in Drosophila. Proc Natl Acad Sci USA 1993;90:4037-41.
15. Weinmaster G. The ins and outs of notch signalling. Mol Cell Neurosci 1997;9:91-102.
16. Matsuno K, Diederich RJ, Go MJ, Blaumueller CM, Artavanis-Tsakonas S. Deltex acts as a positive regulator of Notch signalling through interactions with the Notch ankyrin repeats. Development 1995;121:2633-44.
17. Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD. MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors. Nat Genet 2000;26:484-9.
18. Mumm JS, Kopan R. Notch signalling: from the outside in. Dev Biol 2000;228:151-65.
19. Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 2006;7:678-89.
20. Fiuza UM, Arias AM. Cell and molecular biology of Notch. J Endocrinol 2007; 194:459-74.
21. Jarriault S, Le Bail 0, Hirsinger E, Pourquie 0, Logeat F, Strong CF, et al. Delta-1 activation of notch-1 signalling results in HES-1 transactivation. Mol Cell Biol 1998;18:7423-31.
22. Kuroda K, Tani S, Tamura K, Minoguchi S, Kurooka H, Honjo T. Delta-induced Notch signalling mediated by RBP-J inhibits MyoD expression and myogenesis. J Biol Chem 1999;274:7238-44.
23. Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A. Signalling downstream of activated mammalian Notch [see comments]. Nature 1995;377:355-8.
24. Iso T, Sartorelli V, Chung G, Shichinohe T, Kedes L, Hamamori Y. HERP, a new primary target of Notch regulated by ligandbinding. Mol Cell Biol 2001;21:6071-9.
25. Chang D, Valdez P, Ho T, Robey E. MHC recognition in thymic development: Distinct, parallel pathways for survival and lineage commitment. J Immunol 2000;165:6710-5.
26. Deftos ML, Huang E, Ojala EW, Forbush KA, Bevan MJ. Notch1 signaling promotes the maturation of CD4 and CD8 SP thymocytes. Immunity 2000;13:73-84.
27. Deftos ML, He YW, Ojala EW, Bevan MJ. Correlating Notch signaling with thymocyte maturation. Immunity 1998;9:777-86.
28. Campese AF, Garbe AI, Zhang F, Grassi F, Screpanti I, von Boehmer H. Notch1-dependent lymphomagenesis is assisted by but does not essentially require pre-TCR signaling. Blood 2006;108:305-10.
29. Pirot P, Grunsven LA, Marine JC, Huylebroeck D, Bellefroid EJ. Direct regulation of the Nrarp gene promoter by the Notch signaling pathway. Biochem Biophys Res Comm 2004;322:526-34.
30. Maillard I, Tu L, Sambandam A, Yashiro-Ohtani Y, Millholland J, Keeshan K, et al. The requirement for Notch signaling at the b-selection checkpoint in vivo is absolute and independent of the pre-T cell receptor. J Exp Med 2006;203:2239-45.
31. Amsen D, Blander JM, Lee GR, Tanigaki K, Honjo T, Flavell RA. Instruction of distinct CD4 T helper cell fates by different Notch ligands on antigen-presenting cells. Cell 2004; 117:515-26.
32. Tanaka S, Tsukada J, Suzuki W, Hayashi K, Tanigaki K, Tsuji M, et al. The Interleukin-4 enhancer CNS-2 isregulated by Notch signals and controls initial expression inNKT cells and memory-type CD4 T cells. Immunity 2006;24:689-701.
33. Minter LM, Turley DM, Das P, Shin HM, Joshi I, Lawlor RG, et al. Inhibitors ofgamma-secretase block in vivo and in vitro T helper type 1polarization by preventing Notch upregulation of Tbx21. Nat Immunol 2005;6:680-688.
34. Amsen D, Antov A, Jankovic D, Sher A, Radtke F, Souabni A, et al. Direct regulationof Gata3 expression determines the T helper differentiation potential of Notch. Immunity 2007;27:89-99.
35. Fang TC, Yashiro-Ohtani Y, del Bianco C, Knoblock DM, Blacklow SC, Pear WS. Notch directly regulates Gata3 expression during T helper 2 cell differentiation. Immunity 2007;27:100-110.
36. Ordentlich P, Lin A, Shen CP, Blaumueller C, Matsuno K, Artavanis-Tsakonas S, Notch inhibition of E47 supports the existence of a novel signalling pathway. Mol Cell Biol 1998;18:2230-9.
37. Kojika S, Griffin JD. Notch receptors and hematopoiesis. Exp Hematol 2001;29:1041-52.
38. Washburn T, Schweighoffer E, Gridley T, Chang D, Fowlkes BJ, Cado D, et al. Notch activity influences the alphabeta versus gammadelta T cell lineage decision. Cell 1997;88:833-43.
39. Hasserjian RP, Aster JC, Davi F, Weinberg DS, Sklar J. Modulated expression of notch1 during thymocyte development. Blood 1996;88:970-6.
40. Anderson G, Pongracz J, Parnell S, Jenkinson EJ. Notch ligand-bearing thymic epithelial cells initiate and sustain Notch signaling in thymocytes independently of T cell receptor signalling. Eur J Immunol 2001 ;31:3349-54.
41. Pear W S, Aster J C, Scott M L, Hasserjian R P, Soffer B, Sklar J, et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med 1996; 183:2283-2291.
42. Gothert JR, Brake RL, Smeets M, Duhrsen U, Begley CG, Izon DJ. NOTCH1 pathway activation is an early hallmark of SCL T leukemogenesis. Blood 2007;110(10):3753-62.
43. Wang SF, Aoki M, Nakashima Y, Shinozuka Y, Tanaka H, Taniwaki M, et al. Development of Notch-dependent T-cell leukemia by deregulated Rap1 signaling. Blood 2008;111(5):2878-86.
44. Kindler T, Cornejo MG, Scholl C, Liu J, Leeman DS, Haydu JE, et al. K-RasG12D-induced T-cell lymphoblastic lymphoma/leukemias harbor Notch1 mutations and are sensitive to gamma-secretase inhibitors. Blood 2008;112(8):3373-82.
45. Radtke F, Wilson A, Mancini SJ, MacDonald HR. Notch regulation of lymphocyte development and function. Nat Immunol 2004;5:247-253.
46. Radtke F, Wilson A, MacDonald HR. Notch signaling in hematopoiesis and lymphopoiesis: lessons from Drosophila. BioEssays 2005;27:1117-1128.
47. Radtke F, Wilson A, Stark G, Bauer M, van Meerwijk J, MacDonald HR, et al. Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 1999;10:547-558.
48. HozumiK, Negishi N, Suzuki D, Abe N, Sotomaru Y, Tamaoki N, et al. Delta-like 1 is necessary for the generation of marginal zone B cells but not T cells in vivo. Nat Immunol 2004;5:638-644.
49. Schmitt TM, Zuniga-Pflucker JC. T-cell development, doing it in a dish. Immunol Rev 2006;209:95-102.
50. Rampal R, Li AS, Moloney DJ, Georgiou SA, Luther KB, Nita-Lazar A, et al. Lunatic fringe, manic fringe, and radical fringe recognize similar specificity determinants in O-fucosylated epidermal growth factor-like repeats. J Biol Chem 2005;280:42454-42463.
51. Nie L, Perry SS, Zhao Y, Huang J, Kincade PW, Farrar MA, et al. Regulation of lymphocyte development by cell-type-specific interpretation of Notch signals. Mol Cell Biol 2008;28(6):2078-90.
52. Koch U, Yuan JS, Harper JA, Guidos CJ. Fine-tuning Notch1 activation by endocytosis and glycosylation. Semin Immunol 2003;15:99-106.
53. Wolfer A, Wilson A, Nemir M, MacDonald HR, Radtke F. Inactivation of Notch1 impairs VDJbeta rearrangement and allows pre-TCR-independent survival of early alpha beta Lineage Thymocytes. Immunity 2002; 16:869-879.
54. Ge C, Stanley P. The O-fucose glycan in the ligand-binding domain of Notch1 regulates embryogenesis and T cell development. PNAS 2008;105(5):1539-44.
55. Ciofani M, Schmitt TM, Ciofani A, Michie AM, Cuburu N, Aublin A, et al. Obligatory Role for Cooperative Signaling by Pre-TCR and Notch during Thymocyte Differentiation. J Immunol 2004; 172:5230-5239.
56. Onoyama I, Tsunematsu R, Matsumoto A, Kimura T, de Alboran IM, Nakayama K, et al. Conditional inactivation of Fbxw7 impairs cell-cycle exit during T cell differentiation and results in lymphomatogenesis. J Exp Med 2007;204:2875-2888.
57. Kitamoto T, Takahashi K, Takimoto H, Tomizuka K, Hayasaka M,Tabira T, et al. Functional redundancy of the Notch gene family during mouse embryogenesis: Analysis of Notch gene expression in Notch3-deficient mice. Biochem Biophys Res Comm 2005;331:1154-1162.
58. Vercauteren SM, Sutherland HJ. Constitutively active Notch4 promotes early human hematopoietic progenitor cell maintenance while inhibiting differentiation and causes lymphoid abnormalities in vivo. Blood 2004; 104:2315-2322.
59. Wolfer A, Bakker T, Wilson A, Nicolas M, Ioannidis V, Littman DR, et al. Inactivation of Notch I in immature thymocytes does not perturb CD4 or CD8T cell development. Nature 2001;2:235-241.
60. Plas DR, Thompson CB. Akt-dependent transformation: there is more to growth than just surviving. Oncogene 2005;24:7435-7442.
61. Manning BD, Cantley LC. AKT/PKB Signaling: Navigating Downstream. Cell 2007;129:1261-1274.
62. Toulany M, Baumann M, Rodemann HP. Stimulated PI3K-AKT signaling mediated through ligand or radiation-induced EGFR depends indirectly, but not directly, on constitutive K-Ras activity. Mol Cancer Res 2007;5(8):863-72.
63. Shelton JG, Steelman LS, Abrams SL, White ER, Akula SM, Franklin RA, et al. Conditional EGFR promotes cell cycle progression and prevention of apoptosis in the absence of autocrine cytokines. Cell Cycle 2005;4(6):822-30.
64. Fruman DA. The role of class I phosphoinositide 3-kinase in T-cell function and autoimmunity.Biochem Soc Trans 2007;035:177-180.
65. Andrews S, Stevens LR, Hawkins PT. PI3K class IB pathway. Sci STKE 2007;2007(407):cm2.
66. Fruman DA, Snapper SB, Yballe CM, Davidson L, Yu JY, Alt FW, et al. Impaired B Cell Developmentand Proliferation in Absence of Phosphoinositide 3-Kinase p85. Science 1999;283:393-397.
67. Deane JA, Trifilo MJ, Yballe CM, Choi S, Lane TE, Fruman DA. Enhanced T Cell Proliferation inMice Lacking the p850 Subunit of Phosphoinositide 3-Kinase. J Immunol 2004; 172:6615-6625.
68. Deane JA, Kharas MG, Oak JS, Stiles LN, Luo J, Moore TI, et al. T-cell function is partiallymaintained in the absence of class IA phosphoinositide 3-kinase signaling. Blood 2007; 109:2894-2902.
69. Oak JS, Deane JA, Kharas MG, Luo J, Lane TE, Cantley LC, et al. Sjogren's syndrome-like diseasein mice with T cells lacking class 1A phosphoinositide-3-kinase. Proc Nat Acad Sci USA 2006; 103:16882-16887.
70. Sasaki T, Irie-Sasaki J, Jones RG, Oliveira-dos-Santos AJ, Stanford WL, Bolon B, et al. Function of PI3K in Thymocyte Development, T Cell Activation, and Neutrophil Migration. Science 2000;287:1040-1046.
71. Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, et al. Impaired B and T Cell Antigen Receptor Signaling in p110delta PI 3-Kinase Mutant Mice. Science 2002;297:1031-1034.
72. Webb LMC, Vigorito E, Wymann MP, Hirsch E, Turner M. Cutting Edge: T Cell DevelopmentRequires the Combined Activities of the p110γ and p110δ Catalytic Isoforms of Phosphatidylinositol3-Kinase. J Immunol 2005;175:2783-2787.
73. Swat W, Montgrain V, Doggett TA, Douangpanya J, Puri K, Vermi W, et al. Essential role ofPI3Kδ and PI3Kγ in thymocyte survival. Blood 2006;107:2415-2422.
74. Hagenbeek TJ, Naspetti M, Malergue F, Garcon F, Nunes JA, Cleutjens KBJM, et al. The Loss ofPTEN Allows TCR αβ Lineage Thymocytes to Bypass IL-7 and Pre-TCR-mediated Signaling. J ExpMed 2004;200:883-894.
75. Zinda MJ, Johnson MA, Paul JD, Horn C, Konicek BW, Lu ZH, et al. AKT-1, -2, and -3 are expressed in both normal and tumor tissues of the lung, breast, prostate, and colon. Clin Cancer Res 2001;7(8):2475-9.
76. Juntilla MM, Wofford JA, Bimbaum MJ, Rathmell JC, Koretzky GA. Akt1 and Akt2 are requiredfor αβ thymocyte survival and differentiation. Proc Nat Acad Sci USA 2007;104:12105-12110.
77. Hinton HJ, Clarke RG, Cantrell DA. Antigen receptor regulation of phosphoinositide-dependent kinase 1 pathways during thymocyte development. FEBS Lett 2006;580: 5845-5850.
78. Mao C, Tili EG, Dose M, Haks MC, Bear SE, Maroulakou I, et al. Unequal contribution of akt isoforms in the doublenegativeto double-positive thymocyte transition. J Immunol 2007;178:5443-5453
79. Kelly AP, Finlay DK, Hinton HJ, Clarke RG, Fiorini E, Radtke F, et al. Notch-induced T cell development requires phosphoinositide-dependent kinase 1 EMBO J 2007;26(14):3441-5
80. Hinton HJ, Alessi DR, Cantrell DA. The serine kinase phosphoinositide-dependent kinase 1 (PDK1) regulates T cell development. Nat Immunol 2004;5:539-545.
81. Jones RG, Parsons M, Bonnard M, Chan VSF, Yeh W-C, Woodgett JR, et al. Protein Kinase BRegulates T Lymphocyte Survival, Nuclear Factor k Activation, and Bcl-XL Levels In Vivo. J ExpMed 2000;191:1721-1734.
82. Ciofani M, Zuniga-Pflucker JC. Notch promotes survival of pre-T cells at the β-selection checkpoint by regulating cellular metabolism. Nat Immunol 2005;6:881-888.
83. Zeiser R, Negrin RS. Interleukin-2 receptor downstream events in regulatory T cells: implications for the choice of immunosuppressive drug therapy. Cell Cycle 2008;7(4):458-62.
84. Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci U S A 2008;105(22):7797-802.
85. Aster JC, Xu L, Karnell FG, Patriub V, Pui JC, Pear WS. Essential roles for ankyrin repeat and transactivation domains in induction of T-cell leukemia by notch1. Mol Cell Biol 2000;20:7505-7515.
86. Lee SY, Kumano K, Masuda S, Hangaishi A, Takita J, Nakazaki K et al. Mutations of the Notch1 gene in T-cell acute lymphoblastic leukemia: analysis in adults and children. Leukemia 2005; 19:1841 -1843.
87. Mansour MR, Linch DC, Foroni L, Goldstone AH, Gale RE. High incidence of Notch-1 mutations in adult patients with T-cell acute lymphoblastic leukemia. Leukemia 2006;20:537-539.
88. O'Neil J, Calvo J, McKenna K, Krishnamoorthy V, Aster JC, Bassing CH, et al. Activating Notch1 mutations in mouse models of T-ALL. Blood 2006; 107(2):781-5.
89. Weng AP, Aster JC. Multiple niches for Notch in cancer: context is everything. Curr Opin Genet Dev 2004;14:48-54.
90. Leong KG, Karsan A. Recent insights into the role of Notch signaling in tumorigenesis. Blood 2006; 107:2223-2233.
91. Bellavia D, Campese AF, Checquolo S, Balestri A, Biondi A, Cazzaniga G, et al. Combined expression of pTalpha and Notch3 in T cell leukemia identifies the requirement of preTCR for leukemogenesis. Proc Natl Acad Sci U S A 2002;99:3788-3793.
92. Felli MP, Vacca A, Calce A, Bellavia D, Campese AF, Grillo R, et al. PKC theta mediates pre-TCR signaling and contributes to Notch3-induced T-cell leukemia. Oncogene. 2005;24:992-1000.
93. Sade H, Krishna S, Sarin A. The anti-apoptotic effect of Notch-1 requires p561ck-dependent, Akt/PKB-mediated signaling in T cells. J Biol Chem 2004;279:2937-2944.
94. Guo D, Ye J, Dai J, Li L, Chen F, Ma D, et al. Notch-1 regulates Akt signaling pathway and the expression of cell cycle regulatory proteins cyclin D1, CDK2 and p21 in T-ALL cell lines. Leuk Res 2009;33(5):678-85.
95. Talora C, Campese AF, Bellavia D, Pascucci M, Checquolo S, Groppioni M, et al. Pre-TCR-triggered ERK signalling-dependent downregulation of E2A activity in Notch3-induced T-cell lymphoma. EMBO Rep 2003;4:1067-1072.
96.Mungamuri SK,Yang X,Thor AD,Somasundaram K.Survival signaling by Notch1:mammalian target of rapamycin(mTOR)-dependent inhibition of p53.Cancer Res 2006;66(9):4715-24.
97.Chan SM,Weng AP,Tibshirani R,Aster JC,Utz PJ.Notch signals positively regulate activity of the mTOR pathway in T-cell acute lymphoblastic leukemia.Blood 2007;110(1):278-86.
98.Bellavia D,Campese AF,Alesse E,Vacca A,Felli MP,Balestri A,et al.Constitutive activation of NF-kappaB and T-cell leukemia/lymphoma in Notch3transgenic mice.EMBO J 2000;19:3337-3348.
99.Palomero T,Lim WK,Odom DT,Sulis ML,Real PJ,Margolin A,et al.NOTCH1 directlyregulates c-MYC and activates a feed-forward-loop transcriptional networkpromoting leukemic cell growth.Proc.Natl.Acad.Sci.USA 2006;103:18261-66
100.Lin YW,Nichols RA,Letterio JJ,Aplan PD.Notch1 mutations are important for leukemic transformation in murine models of precursor-T leukemia/lymphoma.Blood 2006;107:2540-3.
101.Zhu YM,Zhao WL,Fu JF,Shi JY,Pan Q,Hu J,et al.NOTCH1 mutations in T-cell acute lymphoblastic leukemia:prognostic significance and implication in multifactorial leukemogenesis.Clin Cancer Res 2006;12(10):3043-9.
102.Mansour MR,Duke V,Foroni L,Patel B,Allen CG,Ancliff PJ,et al.Notch-1mutations are secondary events in some patients with T-cell acute lymphoblastic leukemia.Clin Cancer Res 2007;13(23):6964-9.
103.Cantley LC.The phosphoinositide 3-kinasepathway.Science 2002;296:1655-7
104.Vivanco I,Sawyers CL.Thephosphatidylinositol 3-kinase AKTpathway in human cancer.Nat Rev Cancer 2002;2:489-501.
105.Fry MJ.Phosphoinositide 3-kinasesignalling in breast cancer:how big a role might it play? Breast Cancer Res 2001;3:304-12.
106.Lin X,B(o|¨)hle AS,Dohrmann P,Leuschner I,Schulz A,Kremer B,et al.Overexpression of phosphatidylinositol3-kinase in human lung cancer.Langenbecks Arch Surg 2001;386:293-301.
107.Krasilnikov M, Adler V, Fuchs SY, Dong Z, Haimovitz-Friedman A, Herlyn M, et al. Contribution of phosphatidylinositol3-kinase to radiation resistance in humanmelanoma cells. Mol Carcinog 1999;24:64-9.
108.Martinez-Lorenzo MJ, Anel A, Monleon I, Sierra JJ, Pineiro A, Naval J, et al. Tyrosine phosphorylation of the p85 subunit of phosphatidylinositol3-kinase correlates with high proliferation rates in sublines derived from the Jurkat leukemia. Int J Biochem Cell Biol 2000;32:435-45.
109.Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304:554.
110.Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 2007;448: 39-44.
111. DeGraffenried LA, Fulcher L, Friedrichs WE, Grunwald V, Ray RB, Hidalgo M. Reduced PTEN expression in breast cancer cells confers susceptibility to inhibitors of the PI3kinase/Akt pathway. Ann Oncol 2004;15:1510-6.
112.Hay N. The Akt-mTOR tango and its relevance to cancer. Cancer Cell 2005;8:179-83.
113.Huang HP, Shih YW, Chang YC, Hung CN, Wang CJ. Chemoinhibitory effect of mulberry anthocyanins on melanoma metastasis involved in the Ras/PI3K pathway. J Agric Food Chem 2008;56(19):9286-93.
114.Harir N, Boudot C, Friedbichler K, Sonneck K, Kondo R, Martin-Lanneree S, et al. Oncogenic Kit controls neoplastic mast cell growth through a Stat5/PI3-kinase signaling cascade. Blood 2008;112(6):2463-73.
115.McCubrey JA, Steelman LS, Abrams SL, Lee JT, Chang F, Bertrand FE, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul 2006;46:249-79.
116.Hildebrandt MA, Yang H, Hung MC, Izzo JG, Huang M, Lin J, et al. Genetic variations in the PI3K/PTEN/AKT/mTOR pathway are associated with clinical outcomes in esophageal cancer patients treated with chemoradiotherapy. J Clin Oncol 2009;27(6):857-71.
117.Opitz I, Soltermann A, Abaecherli M, Hinterberger M, Probst-Hensch N, Stahel R, et al. PTEN expression is a strong predictor of survival in mesothelioma patients. Eur J Cardiothorac Surg 2008;33(3):502-6.
118.Zhou L, Huang Y, Li J, Wang Z. The mTOR pathway is associated with the poor prognosis of human hepatocellular carcinoma. Med Oncol 2009.
119.Wu Z, Gioeli D, Conaway M, Weber MJ, Theodorescu D. Restoration of PTEN expression alters the sensitivity of prostate cancer cells to EGFR inhibitors. Prostate 2008;68(9):935-44.
120.Huang WC, Hung MC. Induction of akt activity by chemotherapy confers acquired resistance. J Formos Med Assoc. 2009; 108(3): 180-94.
121.Chen KF, Yeh PY, Hsu C, Hsu CH, Lu YS, Hsieh HP, et al. Bortezomib overcomes TRAIL resistance in hepatocellular carcinoma cells in part through the inhibition of PDK/Akt pathway. J Biol Chem 2009.
122.Cullion K, Draheim KM, Hermance N, Tammam J, Sharma VM, Ware C, et al. Targeting the Notch1 and mTOR pathways in a mouse T-ALL model. Blood 2009.
123.Suzuki A, de la Pompa JL, Stambolic V, Elia AJ, Sasaki T, del Barco Barrantes I, et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr. Biol. Curr Biol 1998;8(21):1169-78.
124.Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM, et al. Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci U S A 1999;96(4): 1563-8.
125.Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP. Pten is essential for embryonic development and tumour suppression. Nat Genet 1998;19(4):348-55.
126.Suzuki A, Yamaguchi MT, Ohteki T, Sasaki T, Kaisho T, Kimura Y, et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity 2001;14(5):523-34.
127.Silva A, Yunes JA, Cardoso BA, Martins LR, Jotta PY, Abecasis M, et al. PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability. J Clin Invest 2008; 118(11):3762-74.
128.Yilmaz OH, Valdez R, Theisen BK, Guo W, Ferguson DO, Wu H, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006;441(7092):475-82.
129.Chang H, Qi XY, Claudio J, Zhuang L, Patterson B, Stewart AK. Analysis of PTEN deletions and mutations in multiple myeloma. Leuk Res 2006;30(3):262-5.
130.Aggerholm A, Gr(?)nbaek K, Guldberg P, Hokland P. Mutational analysis of the tumour suppressor gene MMAC1/PTEN in malignant myeloid disorders. Eur J Haematol 2000;65(2): 109-13.
131.Sakai A, Thieblemont C, Wellmann A, Jaffe ES, Raffeld M. PTEN gene alterations in lymphoid neoplasms. Blood 1998;92(9):3410-5.
132.Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006;7:606-619.
133.Trotman LC, Pandolfi PP. PTEN and p53: who will get the upper hand? Cancer Cell 2003;3:97-99.
134.Sulis ML, Parsons R. PTEN: from pathology to biology. Trends Cell Biol 2003;13(9):478-83.
135.Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 1998;273(22): 13375-8.
136.Hoemann CD, Beaulieu N, Girard L, Rebai N, Jolicoeur P. Two distinct Notch1 mutant alleles are involved in the induction of T-cell leukemia in c-myc transgenic mice. Mol Cell Biol 2000;20(11):3831-42.
137.Feldman BJ, Hampton T, Cleary ML. A carboxy-terminal deletion mutant of Notch1 accelerates lymphoid oncogenesis in E2A-PBX1 transgenic mice. Blood 2000;96(5):1906-13.
138.Weng AP, Nam Y, Wolfe MS, Pear WS, Griffin JD, Blacklow SC, et al. Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Mol Cell Biol 2003;23(2):655-64.
139.Weng AP, Millholland JM, Yashiro-Ohtani Y, Arcangeli ML, Lau A, Wai C, Del Bianco C, et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 2006;20:2096-109.
140.Sharma VM, Calvo JA, Draheim KM, Cunningham LA, Hermance N, Beverly L, et al. Notch1 contributes to mouse T-cell leukemia by directly inducing the expression of c-myc. Mol. Cell. Biol 2006;26:8022-31.
141.Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 1995;378:785-789.
142.Espinosa L, Ingles-Esteve J, Aguilera C, Bigas A. Phosphorylation by glycogen synthase kinase-3 beta down-regulates Notch activity, a link for Notch and Wnt pathways. J Biol Chem 2003;278(34):32227-32235.
143.Foltz DR, Santiago MC, Berechid BE, Nye JS. Glycogen synthase kinase-3beta modulates notch signaling and stability. Curr Biol 2002;12(12):1006-1011.
144.Jin YH, Kim H, Oh M, Ki H, Kim K. Regulation of Notch1 NICD and Hes1 expressions by GSK-3alpha beta. Mol Cells 2009;27(1):15-9.
145.Calzavara E, Chiaramonte R, Cesana D, Basile A, Sherbet GV, Comi P. Reciprocal regulation of Notch and PI3K/Akt signalling in T-ALL cells in vitro. J. Cell. Biochem 2008;103:1405-1412.
146.Bedogni B, Warneke JA, Nickoloff BJ, Giaccia AJ, Powell MB. Notch1 is an effector of Akt and hypoxia in melanoma development. J Clin Invest 2008;118(11):3660-70.
147.Breit S, Stanulla M, Flohr T, Schrappe M, Ludwig WD, Tolle G, et al. Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia. Blood 2006;108:1151-7.
148.Lones MA, Heerema NA, Le Beau MM, Sposto R, Perkins SL, Kadin ME, et al. Chromosome abnormalities in advanced stage lymphoblastic lymphoma of children and adolescents: a report from CCG-E08. Cancer Genet Cytogenet 2007;172:1-11.
149.van Grotel M, Meijerink JP, van Wering ER, Langerak AW, Beverloo HB, Buijs-Gladdines JG, et al. Prognostic significance of molecular-cytogenetic abnormalities in pediatric T-ALL is not explained by immunophenotypic differences. Leukemia 2008;22:124-31.
150.Real PJ, Tosello V, Palomero T, Castillo M, Hernando E, de Stanchina E, et al. Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat Med 2009;15(1):50-8.
[1] De Keersmaecker K, Marynen P, Cools J. Genetic insights in the pathogenesis of T-cell acute lymphoblastic leukemia. Haematologica 2005;90:1116-27.
[2] Graux C, Cools J, Michaux L, Vandenberghe P, Hagemeijer A. Cytogenetics and molecular genetics of T-cell acute lymphoblastic leukemia: from thymocyte to lymphoblast. Leukemia 2006;20:1496-510.
[3] Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004;306:269-71.
[4] Zhu YM, Zhao WL, Fu JF, et al. NOTCH1 mutations in T-cell acute lymphoblastic leukemia: prognostic significance and implication in ultifactorial leukemogenesis. Clin Cancer Res 2006;12:3043-9.
[5] Ellisen LW, Bird J, West DC, et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 1991;66:649-61.
[6] Kogoshi H, Sato T, Koyama T, Nara N, Tohda S. Gamma-secretase inhibitors suppress the growth of leukemia and lymphoma cells. Oncol Rep 2007;18:77-80.
[7] Palomero T, Sulis ML, Cortina M, et al. Mutational loss of PTEN induces resistance to NOTCH 1 inhibition in T-cell leukemia. Nat Med 2007;13:1203-10.
[8] Palomero T, Lim WK, Odom DT, et al. NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci U S A 2006; 103:18261-6.
[9] Sharma VM, Calvo JA, Draheim KM, et al. Notch1 Contributes to Mouse T-Cell Leukemia by Directly Inducing the Expression of c-myc. Mol Cell Biol 2006;26:8022-31.
[10]Iso T, Kedes L, Hamamori Y. HES and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol 2003;194:237-55.
[11]Kageyama R, Ohtsuka T, Hatakeyama J, Ohsawa R. Roles of bHLH genes in neural stem cell differentiation. Exp. Cell Res 2005;306:343-8.
[12]Weng AP, Millholland JM, Yashiro-Ohtani Y, et al. c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 2006;20:2096-109.
[13]Katoh M, Katoh M. Notch signaling in gastrointestinal tract. Int J Oncol 2007; 30:247-51.
[14]Pissarnitski D. Advances in gamma-secretase modulation. Curr Opin Drug Discov Devel 2007; 10:392-402.
[15]Palomero T, Barnes KC, Real PJ, et al. CUTLL1, a novel human T-cell lymphoma cell line with t(7;9) rearrangement, aberrant NOTCH1 activation and high sensitivity to gamma-secretase inhibitors. Leukemia 2006;20:1279-87.
[16]Moussa O, Riker JM, Klein J, Fraig M, Halushka PV, Watson DK. Inhibition of thromboxane synthase activity modulates bladder cancer cell responses to chemotherapeutic agents. Oncogene 2008;27:55-62.
[17]Sherr CJ. G1 phase progression: cycling on cue. Cell 1994;79:551-5.
[18]Dohda T, Maljukova A, Liu L, et al. Notch signaling induces SKP2 expression and promotes reduction of p27Kip1 in T-cell acute lymphoblastic leukemia cell lines. Exp Cell Res. 2007; 313: 3141-3152.
[19] Wang Z, Zhang Y, Li Y, Banerjee S, Liao J, Sarkar FH. Down-regulation of Notch-1 contributes to cell growth inhibition and apoptosis in pancreatic cancer cells. Mol. Cancer Ther 2006;5:483-93.
[20]Ronchini C, Capobianco AJ. Induction of cyclin D1 transcription and CDK2 activity by Notch(ic): implication for cell cycle disruption in transformation by Notch(ic). Mol Cell Biol 2001;21:5925-34.
[21] Li DM, Sun H. PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. Proc Natl Acad Sci U S A 1998;95:15406-11.
[22] Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature 2001 ;411:355-65.
[23]Georgakis GV, Li Y, Rassidakis GZ, Medeiros LJ, Mills GB, Younes A. Inhibition of the phosphatidylinositol-3 kinase/Akt promotes Gl cell cycle arrest and apoptosis in Hodgkin lymphoma. Br J Haematol 2006; 132:503-11.
[24]Mukherji A, Janbandhu VC, Kumar V. GSK-3beta-dependent destabilization of cyclin D1 mediates replicational stress-induced arrest of cell cycle. FEBS Lett 2008;582:1111-6.
[25] He YY, Council SE, Feng L, Chignell CF. UVA-induced cell cycle progression is mediated by a disintegrin and metalloprotease/epidermal growth factor receptor/AKT/Cyclin D1 pathways in keratinocytes. Cancer Res 2008;68:3752-8.
[26]Ikezoe T, Nishioka C, Bandobashi K, et al. Longitudinal inhibition of PI3K/Akt/mTOR signaling by LY294002 and rapamycin induces growth arrest of adult T-cell leukemia cells. Leuk Res 2007;31:673-82.
[27]O'Gorman DM, McKenna SL, McGahon AJ, Cotter TG. Inhibition of PI3-kinase sensitises HL60 human leukaemia cells to both chemotherapeutic drug- and Fas-induced apoptosis by a JNK independent pathway. Leuk Res 2001;25:801-11.
[28] Gutierrez A, Look AT. NOTCH and PI3K-AKT pathways intertwined. Cancer Cell 2007;12:411-3.
[29]Nair P, Somasundaram K, Krishna S. Activated Notch1 inhibits p5 3-induced apoptosis and sustains transformation by human papillomavirus type 16 E6 and E7 oncogenes through a PI3K-PKB/Akt-dependent pathway. J Virol 2003;77:7106-12.
[30]Sade H, Krishna S, Sarin A. The anti-apoptotic effect of Notch-1 requires p561ck-dependent, Akt/PKB-mediated signaling in T cells. J Biol Chem 2004;279:2937-44.
[31]Nefedova Y, Sullivan DM, Bolick SC, Dalton WS, Gabrilovich DI. Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy. Blood 2008; 111:2220-9.
[32]Calzavara E, Chiaramonte R, Cesana D, Basile A, Sherbet GV, Comi P. Reciprocal regulation of Notch and PI3K/Akt signalling in T-ALL cells In Vitro. J Cell Biochem 2008; 103:1405-12.
[33]Breit S, Stanulla M, Flohr T, et al. Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia. Blood 2006; 108:1151-7.
[34]Lones MA, Heerema NA, Le Beau MM, et al. Chromosome abnormalities in advanced stage lymphoblastic lymphoma of children and adolescents: a report from CCG-E08. Cancer Genet Cytogenet 2007;172:1-11.
[35]van Grotel M, Meijerink JP, van Wering ER, et al. Prognostic significance of molecular-cytogenetic abnormalities in pediatric T-ALL is not explained by immunophenotypic differences. Leukemia 2008 ;22:124-31.
1. Liang R, Huang GS, Wang Z, Chen XQ, Bai QX, Zhang YQ, et al. Effects of human bone marrow stromal cell line (HFCL) on the proliferation, differentiation and apoptosis of acute myeloid leukemia cell lines U937, HL-60 and HL-60/VCR. Int J Hematol 2008;87:152-66.
2. Nefedova Y, Cheng P, Alsina M, Dalton WS, Gabrilovich DI. Involvement of Notch-1 signaling in bone marrow stroma-mediated de novo drug resistance of myeloma and other malignant lymphoid cell lines. Blood 2004;103:3503-10.
3. Rothenberg EV. Negotiation of the T lineage fate decision by transcription-factor interplay and microenvironmental signals. Immunity 2007;26:690-702.
4. Fischer A, Gessler M. Delta-Notch-and then? Protein interactions and proposed modes of repression by Hes and Hey bHLH factors. Nucleic Acids Res 2007;35:4583-96.
5. Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD, et al. TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 1991;66:649-61.
6. Weng AP, Nam Y, Wolfe MS, Pear WS, Griffin JD, Blacklow SC, et al. Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. Mol Cell Biol 2003;23:655-64.
7. Weng AP, Ferrando AA, Lee W, Morris JP 4th, Silverman LB, Sanchez-Irizarry C, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 2004;306:269-71.
8. Jang J, Choi YI, Choi J, Lee KY, Chung H, Jeon SH, et al. Notch1 confers thymocytes a resistance to GC-induced apoptosis through Deltexl by blocking the recruitment of p300 to the SRG3 promoter. Cell Death Differ 2006;13:1495-505.
9. Sade H, Krishna S, Sarin A. The anti-apoptotic effect of Notch-1 requires p56~(lck)-dependent, Akt/PKB-mediated signaling in T cells. J Biol Chem 2004;279:2937-44.
10. Mungamuri SK, Yang X, Thor AD, Somasundaram K. Survival signaling by Notch1: mammalian target of rapamycin (mTOR)-dependent inhibition of p53. Cancer Res 2006;66:4715-24.
11. Nefedova Y, Sullivan DM, Bolick SC, Dalton WS, Gabrilovich DI. Inhibition of Notch signaling induces apoptosis of myeloma cells and enhances sensitivity to chemotherapy. Blood 2008; 111:2220-29.
12. Kogoshi H, Sato T, Koyama T, Nara N, Tohda S. Gamma-secretase inhibitors suppress the growth of leukemia and lymphoma cells. Oncol Rep 2007; 18:77-80.
13. Katoh M, Katoh M. Notch signaling in gastrointestinal tract. Int J Oncol 2007;3:247-51.
14. Pissarnitski D. Advances in gamma-secretase modulation. Curr Opin Drug Discov Devel 2007; 10:392-402.
15. Lagneaux L, Delforge A, Bron D, De Bruyn C, Stryckmans P. Chronic lymphocytic leukemic B cells but not normal B cells are rescued from apoptosis by contact with normal bone marrow stromal cells. Blood 1998;91:2387-96.
16. Dankbar B, Padro T, Leo R, Feldmann B, Kropff M, Mesters RM, et al. Vascular endothelial growth factor and interleukin-6 in paracrine tumor-stromal cell interactions in multiple myeloma. Blood 2000;95:2630-6.
17. Tabe Y, Jin L, Tsutsumi-Ishii Y, Xu Y, McQueen T, Priebe W, et al. Activation of integrin-linked kinase is a critical prosurvival pathway induced in leukemic cells by bone marrow-derived stromal cells. Cancer Res 2007;67:684-94.
18. Winter SS, Sweatman J, Shuster JJ, Link MP, Amylon MD, Pullen J, et al. Bone marrow stroma-supported culture of T-lineage acute lymphoblastic leukemic cells predicts treatment outcome in children: a Pediatric Oncology Group study. Leukemia 2002;16:1121-6.
19. Scupoli MT, Perbellini O, Krampera M, Vinante F, Cioffi F, Pizzolo G. Interleukin 7 requirement for survival of T-cell acute lymphoblastic leukemia and human thymocytes on bone marrow stroma. Haematologica 2007;92:264-6.
20. Rutz S, Mordmuller B, Sakano S, Scheffold A. Notch ligands Delta-likel, Delta-like4 and Jagged1 differentially regulate activation of peripheral T helper cells. Eur J Immunol 2005; 35:2443-51.
21. Bash J, Zong WX, Banga S, Rivera A, Ballard DW, Ron Y, et al. Rel/NF-kappaB can trigger the Notch signaling pathway by inducing the expression of Jagged1, a ligand for Notch receptors. EMBO J 1999;18:2803-l 1.
22. Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M, et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 2007;13:1203-10.
23. Rangarajan A, Syal R, Selvarajah S, Chakrabarti O, Sarin A, Krishna S. Activated Notch1 signaling cooperates with papillomavirus oncogenes in transformation and generates resistance to apoptosis on matrix withdrawal through PKB/Akt. Virology 2001;286:23-30.
24. Nair P, Somasundaram K, Krishna S. Activated Notch1 inhibits p53-induced apoptosis and sustains transformation by human papillomavirus type 16 E6 and E7 oncogenes through a PI3K-PKB/Akt-dependent pathway. J Virol 2003;77:7106-12.
25. Bheeshmachar G, Purushotaman D, Sade H, Gunasekharan V, Rangarajan A, Sarin A. Evidence for a role for notch signaling in the cytokine-dependent survival of activated T cells. J Immunol 2006;177:5041-50.
26. Foltz DR, Santiago MC, Berechid BE, Nye JS. Glycogen synthase kinase-3beta modulates notch signaling and stability. Curr Biol 2002;12:1006-11.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |