急性白血病患者PTEN的表达情况及其机制研究
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摘要
第一部分利用定量流式细胞术比较PTEN在急性白血病患者和正常人中的表达差异
目的:研究肿瘤抑制基因PTEN在急性白血病患者和正常人骨髓细胞中的表达情况,并比较其差异。
方法:收集36例初发急性白血病患者和5例正常人的骨髓细胞,利用定量流式细胞术,通过Kolmogorov-Smirnov (KS)分析,检测PTEN表达情况。
结果:正常人骨髓淋巴细胞、粒细胞、单核细胞PTEN表达的D值分别为(0.93±0.05),(0.97±0.02)和(0.95±0.03)。36例初发的急性白血病患者中,26例急性髓细胞白血病(AML)患者(1例M0,2例M1,11例M2,3例M3,6例M4,2例M5,1例M6)的骨髓原始细胞均检测到PTEN的表达,除1例M4和2例M5患者PTEN表达与正常对照组的接近,其余患者PTEN表达均较正常对照组降低,但是各个样本PTEN的表达表现出很大的差异性。8例急性B淋巴细胞白血病(B-ALL)患者的骨髓原始细胞PTEN的表达明显缺失,D值为(0.51±0.05)。2例急性T淋巴细胞白血病(T-ALL)患者的骨髓原始细胞PTEN表达的D值为( 0.74±0.02)。
结论:1.AML患者骨髓原始细胞均检测到PTEN的表达,但较正常对照组下调,且各个样本PTEN的表达表现出很大的差异性。AML患者骨髓原始细胞PTEN表达和FAB分型之间的联系是否具有统计学意义还需进一步研究。2.PTEN的表达明显下调或缺失在B-ALL中是一个常见现象。
第二部分B-ALL患者PTEN表达缺失及其启动子甲基化状态关系的研究
目的:探讨抑癌基因PTEN在急性B淋巴细胞白血病(B-ALL)患者外周血单个核细胞中的表达缺失及其与启动子甲基化状态之间的关系。
方法: 24例初发B-ALL患者的外周血单个核细胞和25例正常人外周血单个核细胞,利用定量流式细胞术,通过Kolmogorov-Smirnov (KS)分析,检测PTEN表达情况后,提取基因组DNA,采用MSP方法检测PTEN启动子甲基化状态。进而将外周血单个核细胞在体外培养过程中,以DNA甲基化转移酶抑制剂5-氮-2’脱氧胞嘧啶进行处理,观察其对B-ALL标本中PTEN的表达的影响。
结果:25例健康供者外周血单个核细胞均表达PTEN,KS分析时D值为0.941±0.017,而24例B-ALL患者中22例(91.6%)外周血单个核细胞PTEN的表达明显缺失,D值仅为0.546±0.115,两者差异具有显著性意义(P<0.01);正常人和PTEN高表达的B-ALL患者外周血单个核细胞中未发现PTEN启动子发生甲基化修饰,而PTEN表达缺失的B-ALL患者中有5例(22.7%)出现PTEN启动子甲基化,将其单个核细胞培养时以5-氮-2’脱氧胞嘧啶处理4天,PTEN表达得以明显升高。
讨论:1.PTEN的表达明显下调或缺失在B-ALL中很常见2.PTEN启动子甲基化导致的PTEN表达缺失对B-ALL的发生可能起到重要的作用。
第三部分STI571治疗2例携带e19a2的加速期CML患者的细胞遗传学改变
目的:研究携带e19a2融合转录方式CML患者的临床特征及其与临床预后之间的关系,以及STI571对其治疗的效果。
方法:两例加速期CML患者行STI571治疗,检测e19a2的表达情况,并定期进行骨髓细胞遗传学、巢式RT-PCR、FISH检测。
结果:两例患者均携带e19a2,第1例患者经9个月的STI571治疗(600mg/天)后,细胞遗传学检查未见Ph染色体,巢式RT-PCR也仅检测到极少量的e19a2融合基因。第2例患者经6个月的STI571治疗(600mg/天)后,细胞遗传学检查未见Ph染色体和+der(22)t(9;22),通过FISH仅在5%的间期核中检测到+der(22)t(9;22)。
讨论:1.e19a2可能与临床预后不良的CML相关联。
2.STI571治疗对加速期的携带e19a2的患者依然有效。
PARTⅠA Comparison of PTEN Expression Difference on Both Normal Person and Acute Leukemia Patients by Quantitative Flow Cytometry Analysis
Objective To study and comparison of a novel tumor suppressor gene PTEN expression difference on bone marrow cells from both healthy person and acute leukemia patients Methods Bone marrow cell samples were Collected form both 5 normal donors and 36 primary acute leukemia patients, Used Kolmogorov– Smirnov (KS) statistical test to characterize the expression of PTEN in quantitative flow cytometry analysis.
Results Lymphocytes, granulocytes and monocytes of five normal bone marrow samples showed comparable levels of PTEN expression, with average D-values of 0.93±0.05, 0.97±0.02, and 0.95±0.03, respectively. By the test of Bone marrow blast cell simples from 36 primary acute leukemia patients, PTEN expression could be detected In the 26 patients with de novo AML (1 M0, 2 M1, 11 M2, 3 M3, 6 M4, 2 M5 and 1 M6) simples tested. Except 1 M4 and 2 M5 patents samples showed approximate PTEN expression level compared with Normal samples, PTEN expression level of other Patient samples significantly lowers than that in normal cell populations. Whereas, particularly PTEN expression difference was detected in samples tested. 8 B-ALL patient samples showed spectacularly low down PTEN expression level with D-values of 0.51±0.05. compared with normal samples. 2 T-ALL patients samples with D-values of 0.74±0 02.
Conclusion 1. All AML patients showed perceptible PTEN expression whereas particularly low level than normal samples, differences observed in samples respectively.
This observation needs to be validated in more patients, and its implications should be further investigated whether PTEN expression level correlated with leukemia FAB subtype.
2. absent/low PTEN expression is a frequent event in B-ALL.
PARTⅡThe Investigation of PTEN Expression and Its Promoter Methylation in B-ALL Patients
Objective To study the expression of tumor suppressor PTEN in peripheral blood mononuclear cells of B-ALL patients and involvement of promoter methylation in the loss of PTEN expression in these patients.
Methods Kolmogorov– Smirnov (KS) statistical test was used to characterize the expression of PTEN in peripheral blood mononuclear cells from both healthy donors and B-ALL patients in quantitative flow cytometry analysis. PTEN Promoter Methylation status of genomic DNA extracted from the peripheral blood mononuclear cells was determinded by MSP analysis.The peripheral blood mononuclear cells were treated with 5-Aza-2’deoxycytidine for 4 days to study its effect on restoring PTEN expression in B-ALL peripheral blood mononuclear cells.
Resuits Compared with the high level PTEN expression in healthy donors(D value 0.941±0.017), PTEN expression could barely be detected in 22(91.6%) B-ALL patients ( D value 0.546±0.115). PTEN Promoter Methylation was detected in 5 B-ALL patients(22.7%)but not in any healthy donor. Moreover, 5-Aza-2’deoxycytidine treatment could restore the PTEN epxression in these patients.
Conclusion 1.Low/absent expression of PTEN is a frequent event in B-ALL patients
2.promoter Methylation should contribute to the loss of PTEN epression in some of B-ALL patients.
PartⅢThe Investigation of Early Cytogenetic Response to Imatinib in Two Patients with CML at Accelerated Phase and Carrying the e19a2 BCR-ABL Transcript
Objective To study implications of e19a2 and CML clinic prognosis, and Imatinib’s therapeutic effect on CML patients with e19a2 transcripts
Method 2 accelerated phase CML patients had been treated by STI571 and tested with e19a2 expression. Periodic Bone Marrow Cytogenetic Analysis, Nested Reverse Transcription Polymerase Chain Reaction Analysis and FISH Analysis also included. Results e19a2 expression detected in 2 patient samples at first begin. No Ph chromosome detected in sample of No.1 Patient by cytogenetic analysis after 9 months STI571 treatment (600mg/Day), only very small quantity of e19a2 fused gene was detected in sample. The other patient was treated by STI571 for 6 months (600mg/Day), no Ph chromosome and +der(22)t(9;22) detected by cytogenetic analysis, +der(22)t(9;22) was detected in only 5% Interphase nuclei.
Conclusion 1.the presence of e19a2 transcript might be associated with a unfavorable prognosis in CML.
2.imatinib treatment could be also valuable for CML patients with e19a2 rearrangements, even in accelerated phase.
目的:研究肿瘤抑制基因PTEN在急性白血病患者和正常人骨髓细胞中的表达情况,并比较其差异。
方法:收集36例初发急性白血病患者和5例正常人的骨髓细胞,利用定量流式细胞术,通过Kolmogorov-Smirnov (KS)分析,检测PTEN表达情况。
结果:正常人骨髓淋巴细胞、粒细胞、单核细胞PTEN表达的D值分别为(0.93±0.05),(0.97±0.02)和(0.95±0.03)。36例初发的急性白血病患者中,26例急性髓细胞白血病(AML)患者(1例M0,2例M1,11例M2,3例M3,6例M4,2例M5,1例M6)的骨髓原始细胞均检测到PTEN的表达,除1例M4和2例M5患者PTEN表达与正常对照组的接近,其余患者PTEN表达均较正常对照组降低,但是各个样本PTEN的表达表现出很大的差异性。8例急性B淋巴细胞白血病(B-ALL)患者的骨髓原始细胞PTEN的表达明显缺失,D值为(0.51±0.05)。2例急性T淋巴细胞白血病(T-ALL)患者的骨髓原始细胞PTEN表达的D值为( 0.74±0.02)。
结论:1.AML患者骨髓原始细胞均检测到PTEN的表达,但较正常对照组下调,且各个样本PTEN的表达表现出很大的差异性。AML患者骨髓原始细胞PTEN表达和FAB分型之间的联系是否具有统计学意义还需进一步研究。2.PTEN的表达明显下调或缺失在B-ALL中是一个常见现象。
第二部分B-ALL患者PTEN表达缺失及其启动子甲基化状态关系的研究
目的:探讨抑癌基因PTEN在急性B淋巴细胞白血病(B-ALL)患者外周血单个核细胞中的表达缺失及其与启动子甲基化状态之间的关系。
方法: 24例初发B-ALL患者的外周血单个核细胞和25例正常人外周血单个核细胞,利用定量流式细胞术,通过Kolmogorov-Smirnov (KS)分析,检测PTEN表达情况后,提取基因组DNA,采用MSP方法检测PTEN启动子甲基化状态。进而将外周血单个核细胞在体外培养过程中,以DNA甲基化转移酶抑制剂5-氮-2’脱氧胞嘧啶进行处理,观察其对B-ALL标本中PTEN的表达的影响。
结果:25例健康供者外周血单个核细胞均表达PTEN,KS分析时D值为0.941±0.017,而24例B-ALL患者中22例(91.6%)外周血单个核细胞PTEN的表达明显缺失,D值仅为0.546±0.115,两者差异具有显著性意义(P<0.01);正常人和PTEN高表达的B-ALL患者外周血单个核细胞中未发现PTEN启动子发生甲基化修饰,而PTEN表达缺失的B-ALL患者中有5例(22.7%)出现PTEN启动子甲基化,将其单个核细胞培养时以5-氮-2’脱氧胞嘧啶处理4天,PTEN表达得以明显升高。
讨论:1.PTEN的表达明显下调或缺失在B-ALL中很常见2.PTEN启动子甲基化导致的PTEN表达缺失对B-ALL的发生可能起到重要的作用。
第三部分STI571治疗2例携带e19a2的加速期CML患者的细胞遗传学改变
目的:研究携带e19a2融合转录方式CML患者的临床特征及其与临床预后之间的关系,以及STI571对其治疗的效果。
方法:两例加速期CML患者行STI571治疗,检测e19a2的表达情况,并定期进行骨髓细胞遗传学、巢式RT-PCR、FISH检测。
结果:两例患者均携带e19a2,第1例患者经9个月的STI571治疗(600mg/天)后,细胞遗传学检查未见Ph染色体,巢式RT-PCR也仅检测到极少量的e19a2融合基因。第2例患者经6个月的STI571治疗(600mg/天)后,细胞遗传学检查未见Ph染色体和+der(22)t(9;22),通过FISH仅在5%的间期核中检测到+der(22)t(9;22)。
讨论:1.e19a2可能与临床预后不良的CML相关联。
2.STI571治疗对加速期的携带e19a2的患者依然有效。
PARTⅠA Comparison of PTEN Expression Difference on Both Normal Person and Acute Leukemia Patients by Quantitative Flow Cytometry Analysis
Objective To study and comparison of a novel tumor suppressor gene PTEN expression difference on bone marrow cells from both healthy person and acute leukemia patients Methods Bone marrow cell samples were Collected form both 5 normal donors and 36 primary acute leukemia patients, Used Kolmogorov– Smirnov (KS) statistical test to characterize the expression of PTEN in quantitative flow cytometry analysis.
Results Lymphocytes, granulocytes and monocytes of five normal bone marrow samples showed comparable levels of PTEN expression, with average D-values of 0.93±0.05, 0.97±0.02, and 0.95±0.03, respectively. By the test of Bone marrow blast cell simples from 36 primary acute leukemia patients, PTEN expression could be detected In the 26 patients with de novo AML (1 M0, 2 M1, 11 M2, 3 M3, 6 M4, 2 M5 and 1 M6) simples tested. Except 1 M4 and 2 M5 patents samples showed approximate PTEN expression level compared with Normal samples, PTEN expression level of other Patient samples significantly lowers than that in normal cell populations. Whereas, particularly PTEN expression difference was detected in samples tested. 8 B-ALL patient samples showed spectacularly low down PTEN expression level with D-values of 0.51±0.05. compared with normal samples. 2 T-ALL patients samples with D-values of 0.74±0 02.
Conclusion 1. All AML patients showed perceptible PTEN expression whereas particularly low level than normal samples, differences observed in samples respectively.
This observation needs to be validated in more patients, and its implications should be further investigated whether PTEN expression level correlated with leukemia FAB subtype.
2. absent/low PTEN expression is a frequent event in B-ALL.
PARTⅡThe Investigation of PTEN Expression and Its Promoter Methylation in B-ALL Patients
Objective To study the expression of tumor suppressor PTEN in peripheral blood mononuclear cells of B-ALL patients and involvement of promoter methylation in the loss of PTEN expression in these patients.
Methods Kolmogorov– Smirnov (KS) statistical test was used to characterize the expression of PTEN in peripheral blood mononuclear cells from both healthy donors and B-ALL patients in quantitative flow cytometry analysis. PTEN Promoter Methylation status of genomic DNA extracted from the peripheral blood mononuclear cells was determinded by MSP analysis.The peripheral blood mononuclear cells were treated with 5-Aza-2’deoxycytidine for 4 days to study its effect on restoring PTEN expression in B-ALL peripheral blood mononuclear cells.
Resuits Compared with the high level PTEN expression in healthy donors(D value 0.941±0.017), PTEN expression could barely be detected in 22(91.6%) B-ALL patients ( D value 0.546±0.115). PTEN Promoter Methylation was detected in 5 B-ALL patients(22.7%)but not in any healthy donor. Moreover, 5-Aza-2’deoxycytidine treatment could restore the PTEN epxression in these patients.
Conclusion 1.Low/absent expression of PTEN is a frequent event in B-ALL patients
2.promoter Methylation should contribute to the loss of PTEN epression in some of B-ALL patients.
PartⅢThe Investigation of Early Cytogenetic Response to Imatinib in Two Patients with CML at Accelerated Phase and Carrying the e19a2 BCR-ABL Transcript
Objective To study implications of e19a2 and CML clinic prognosis, and Imatinib’s therapeutic effect on CML patients with e19a2 transcripts
Method 2 accelerated phase CML patients had been treated by STI571 and tested with e19a2 expression. Periodic Bone Marrow Cytogenetic Analysis, Nested Reverse Transcription Polymerase Chain Reaction Analysis and FISH Analysis also included. Results e19a2 expression detected in 2 patient samples at first begin. No Ph chromosome detected in sample of No.1 Patient by cytogenetic analysis after 9 months STI571 treatment (600mg/Day), only very small quantity of e19a2 fused gene was detected in sample. The other patient was treated by STI571 for 6 months (600mg/Day), no Ph chromosome and +der(22)t(9;22) detected by cytogenetic analysis, +der(22)t(9;22) was detected in only 5% Interphase nuclei.
Conclusion 1.the presence of e19a2 transcript might be associated with a unfavorable prognosis in CML.
2.imatinib treatment could be also valuable for CML patients with e19a2 rearrangements, even in accelerated phase.
引文
1. Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science , 1997,275: 1943–1947.
2. Lee JO , Yang H , Georgescu MM , et al .Crystal structure of the PTEN tumor suppressor :implications for its phosphoinositide phosphatase activity and membrane association . Cell , 1999 , 99 ( 3) :323-334.
3. Cantley LC , Neel BC. New insight into tumor suppression : PTEN suppresses tumor formation by restraining the phosphoinositide 32kinase/ AKT pathway. Proc Natl Acad Sci USA. 1999 , 96∶4240～4245.
4. Duerr, E. M., Rollbrocker, et al . PTEN mutations in gliomas and glioneuronal tumors. Oncogene, 16: 2259–2264, 1998.
5. Tsao, H. S., Zhang, X., et al .Identification of PTEN/MMAC 1 alterations in uncultured melanomas and melanoma cell lines. Oncogene, 16: 3397–3402, 1998.
6. Perren, A., Weng, L-P., Boag, et al .Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. Am. J. Pathol., 155:1254–1260, 1999.
7. Cairns, P., Okami, K., Halachmi, S., et al .Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res., 57: 4997–5000, 1997.
8. Mutter, G. L., Lin, et al .Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J. Natl. Cancer Inst. (Bethesda), 92: 924–930, 2000.
9. Kondo, K., Yao, M., Kobayashi, et al . PTEN/MMAC1/TEP1 mutations in human primary renal-cell carcinomas and renal carcinoma cell lines. Int. J. Cancer, 91: 219–224, 2001.
10. Martelli AM, Nyakern M, Tabellini G, et al. Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia. Leukemia 2006. 20: 911–928.
11. Xu Q, Simpson S. E,Scialla T. J, et al. Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood, 2003,102: 972–980.
12. Grandage V. L, Gale R. E, Linch D. C, et al. PI3-kinase/Akt is constitutively active inprimary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-ΚB, Mapkinase and p53 pathways. Leukemia ,2005, 19: 586–594.
13. Cheong JW, Eom JI, Maeng HY, et al. Phosphatase and tensin homologue phosphorylation in the C-terminal regulatory domain is frequently observed in acute myeloid leukaemia and associated with poor clinical outcome. Br J Haematol 2003. 122: 454–456.
14. Min YH, Cheong JW, Lee MH, et al. Elevated S-phase kinase-associated protein 2 protein expression in acute myelogenous leukemia: its association with constitutive phosphorylation of phosphatase and tensin homologue protein and poor prognosis. Clin Cancer Res 2004. 10: 5123–5130.
15. Zhang J, Grindley JC, Yin T, Jayasinghe S, He XC, Ross JT et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 2006. 441:518–522.
16. 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: 475–482.
17. Zhou M, Gu L, Findley HW, Jiang R, Woods WG. PTEN reverses MDM2-mediated chemotherapy resistance by interacting with p53 in acute lymphoblastic leukemia cells. Cancer Res 2003; 63:6357–6362.
1. Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science ,1997,275: 1943–1947.
2. Cantley LC , Neel BC. New insight into tumor suppression : PTEN suppresses tumor formation by restraining the phosphoinositide 32kinase/ AKT pathway. Proc Natl Acad Sci USA. 1999 , 96∶4240～4245.
3. Duerr, E. M., Rollbrocker, et al . PTEN mutations in gliomas and glioneuronal tumors. Oncogene, 16: 2259–2264, 1998.
4. Tsao, H. S., Zhang, X., et al .Identification of PTEN/MMAC 1 alterations in uncultured melanomas and melanoma cell lines. Oncogene, 16: 3397–3402, 1998.
5. Perren, A., Weng, L-P., Boag, et al .Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. Am. J. Pathol., 155: 1254–1260, 1999.
6. Cairns, P., Okami, K., Halachmi, S., et al .Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res., 57: 4997–5000, 1997.
7. Mutter, G. L., Lin, et al .Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J. Natl. Cancer Inst. (Bethesda), 92: 924–930, 2000.
8. Kondo, K., Yao, M., Kobayashi, et al . PTEN/MMAC1/TEP1 mutations in human primary renal-cell carcinomas and renal carcinoma cell lines. Int. J. Cancer, 91: 219–224, 2001.
9.元云飞,李锦清,杨祖立,等.肿瘤相关基因过甲基化的研究进展[J].癌症,2002,21(11):1267-1277.
10. Jean-Charles Soria, Ho-Young Lee, Janet I. Lee, et al. Lack of PTEN Expression in Non-Small Cell Lung Cancer Could Be Related to Promoter Methylation. Clinical Cancer Research ,2002 May, 8(5): 1178–1184.
11. James G. hermans,Jeremy R.Graff,Barry D. Nelkin, et al. Methylation-specific PCR: A novel PCR assay for methylation status of CpG islands. PNAS,1996,93:9821-9826 Xu Q, Simpson S. E,Scialla T. J, et al. Survival of acute myeloid leukemia cellsrequires PI3 kinase activation. Blood, 2003,102: 972–980.
12. Grandage V. L, Gale R. E, Linch D. C, et al. PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-ΚB, Mapkinase and p53 pathways. Leukemia ,2005, 19: 586–594.
13. Zhang J, Grindley JC, Yin T, Jayasinghe S, He XC, Ross JT et al. PTEN maintains
14. haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 2006. 441:518–522.
15. Yilmaz OH, Valdez R, Theisen BK, et al. PTEN dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006. 441: 475–482.
16. Whang YE, Wu X, Suzuki H, et al. Inactivation of the tumor suppressor PTEN/ MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci USA 1998;95:5246–50.
17. Ajay Goel, Christian N. Arnold, Donna Niedzwiecki, et al. Frequent Inactivation of PTEN by Promoter Hypermethylation in Microsatellite Instability-High Sporadic Colorectal Cancers Cancer Reserch, 2004 May 1 (64):3014–3021
18. Brognard J, Clark A. S., Ni, Y., and Dennis P. A. Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res., 61: 3986–3997, 2001.
19. Kauffmann-Zeh, A., Rodriguez-Viciana, P., Ulrich, E., et al. Suppression of c-Myc-induced apoptosis by Ras signaling through PI3K and PKB. Nature (Lond.), 385: 544–548, 1997.
20. Khwaja, A., Rodriguez-Viciana, P., Wennstrom, S., et al. Matrix adhesion and ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J., 16: 2783–2793, 1997.
21. Chen, R. H., Su, Y. H., Chuang, R. L., and Chang. T. Y. Suppression of transforming growth factor-β-induced apoptosis through a phosphatidylinositol 3-kinase/ Akt - dependent pathway. Oncogene, 17:1959–1968, 1998.
1.张之南主编.血液病诊断及疗效标准,第二版.北京:科学出版社.1998
2.彭孝廉.CML的诊断和鉴别诊断.中国医刊,1999,34(9):5
3. Melo JV, The molecular biology of chronic myeloid leukemia, Leukemia, 1996, 10: 751
4. Melo JV, Gordon DE, Cross NCP, et al. The ABL-BCR fusion gene is expressedin chronic myeloid leukemia. Blood, 1993,81: 158
5. Cortes JE, Talpaz M, Beran M, et al. Philadelphia chromosome– negative chronic myelogenous leukemia with rearrangement of the breakpoint cluster region. Cancer, 1995, 75:464
6. Saglio G, Guerrasio A, Rosso C, et al. New type of Bcr/Abl junction in Philadelphia chromosome-positive chronic myelogenous leukemia. Blood 1990;76:1819–24.
7. Pane F, Frigeri F, Sindona M, et al. Neutrophilic-chronic myeloid leukemia: a distinct disease with a specific molecular marker (BCR/ABL with C3/A2 junction). Blood 1996;88:2410–14.
8. Martinez-Lopez J, Ayala R, Albizua Q. Typical chronic myelogenous leukemia with e19a2 BCR/ABL transcript. Report of two cases. Haematologica 2002;87:ELT35.
9. Ohsaka A, Hoshino S, Kobayashi M, Kudo H, Kawaguchi R. Blast crisis of Philadelphia chromosome-positive chronic myeloid leukaemia carrying micro-bcr breakpoint (e19a2 and e191a). British Journal of Haematology 2002;118:251-4.
10. Lee JJ, Kim HJ, Kim YJ, Lee S, Hwang JY. Imatinib induces a cytogenetic response in blast crisis or interferon failure chronic myeloid leukemia patients with e19a2 BCR- ABL transcripts. Leukemia 2004;18:1539-40.
11. Mondal BC, Majumdar S, Dasgupta UB, Chaudhuri U, Chakrabarti P, Bhattacharyya S. e19a2 BCR-ABL fusion transcript in typical chronic myeloid leukaemia: a report of two cases. Journal of Clinical Pathology 2006;59:1102-3.
12. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM. Efficacy and safety of an abl specific tyrosine kinase inhibitor as targeted therapy for chronic myeloid leukemia. New England Journal of Medicine 2001;344:1031–7.
13. Hughes TP, Morgan GJ, Martiat P, Goldman JM. Detection of residual leukemia after bone marrow transplant for chronic myeloid leukemia: role of polymerase chain reaction in predicting relapse. Blood 1991;77:874-8.
14. Sinclair PB, Nacheva EP, Leversha M, Telford N, Chang J, Reid A. Large deletions at the t(9;22) breakpoint are common and may identify a poor-prognosis subgroup of patients with chronic myeloid leukemia. Blood 2000;95:738-43.
15.全国白血病与再生障碍性贫血流行病学调查协作组.全国白血病发病情况调查.中国医学科学院学报,1992,14(1):12
16. Kantarjian HM, Talpaz M, O'Brien S, Smith TL, Giles FJ, Faderl S. Treatment of philadelphia chromosome-positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clinical Cancer Research 2002;8:2167-76.
1. Bostrom J, Cobbers JM,Wolter M , et al . Mutation of the PTEN (MMAC1) tumor suppressor gene in a subset of glioblastomas but not in meningiomas with loss of chromosome arm 10q. Science ,1997 ,275 :1943-1947.
2. Steck PA ,Pershous MA ,Jasser SA , et al . Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet ,1997 ,15 :356.
3. Li DM,Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res, 1997 , 57 :2124-2129.
4. Leslie NR,Gray A, Pass I,Aet al. Analysis of the cellular functions of PTEN using catalytic domain and C-terminal mutations: differential effects of C-terminal deletion on signalling pathways downstream of phosphoinositide 3-kinase. Biochem J. 2000 Mar 15;346 Pt 3:827-33.
5. Myers MP ,Stolarov JP ,Eng C , et al . P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci USA ,1997 , 94 : 9052-9057
6. Tolkacheva T,Chan AM. Inhibition of H-Ras transformation by the PTEN/MMAC1/ TEP1 tumor suppressor gene. Oncogene. 2000 Feb 3;19(5):680-9.
7. Iijima M, Huang YE , Luo HR et al . Novel mechanism of PTEN regulation by its phosphatidylinositol 4 ,5-bisphosphate binding motif is critical for chemotaxis[J ] . J Biol Chem , 2004 , 279 (16) :16606 -16613.
8. Lee JO , Yang H , Georgescu MM, et al . Crystal structure of the PTEN tumor suppressor : implications for its phosphoinositide phosphatase activity and membrane association[J ] . Cell , 1999 , 99 (3) :323 - 334.
9. Raftopoulou M, Etienne-Manneville S , Self A , et al . Regulation of cell migration by the C2 domain of the tumor suppressor PTEN[J ] . Science , 2004 , 303 (5661) :1179 - 1181.
10. Valiente M, Andres-Pons A , Gomar B , et al . Binding of PTEN to specific PDZdomains contributes to PTEN protein stability and phosphorylation by microtubule- associated serine/ threonine kinases[J ] . J Biol Chem , 2005 , 280 (32) :28936 - 28943.
11. Miller SJ , Lou DY, Seldin DC , et al . Direct identification of PTEN phosphorylation sites[J ] . FEBS Letters , 2002 , 528 :145 - 153.
12. Sumitomo M, Iwase A, Zheng R, et al. Synergy in tumor supp ression by direct inter- action of neutral endopep tidase with PTEN[ J ]. Cancer Cell, 2004, 5 (1) : 67-78.
13. Gao X, Neufeld Tp, Pan D. Drosophila PTEN regulates cell growth and proliferation through PI3K-dependent and -independent pathways.Dev Biol, 2000 May 15; 221 (2) :404-18.
14. Yokoyama Y, Wan X, Shinohara A, et al. Expression of PTEN and PTEN pseudogene in endometrial carcinoma. Int J Mol Med. 2000 Jul; 6 (1) :47-50.
15. Teng DH, Hu R, Lin H, et al. MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res, 1997 Dec 1;57(23):5221-5.
16. Steck PA, Pershouse MA, Jasser, et, al. Identification of a candidate tumor suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers [J ], Nat Genet, 1997,15 (4 ) :356 - 363
17. Furnari FB, Lin H, Huang H , et al . Growth suppression of glioma cells by PTEN re- quires a functional phosphatase catalytic domain.Proc Natl Acad Sci USA , 1997, 94:1247 9-12484.
18. Stocker H, AndjelkovicM, Oldham S, et al. Living with lethal PIP3 levels: viability of flies lacking PTEN restored by a pH domain mutation in AKT/PKB [ J ]. Science, 2002, 1295 (5562) : 2088-2091.
19. Robertson GP , Furnari FB ,Miele ME , et al . In vitro loss of heterozygosity targets the PTEN/MMAC1 gene in melanoma. Proc Natl Acad Sci USA ,1998 ,95 :9418-9423.
20. Kang-Park S, Lee YI, Lee YI, et al. PTEN modulates insulin-like growth factorⅡ( IGF-Ⅱ)-mediated signaling : the protein phosphatase activity of PTEN downregulates IGF-Ⅱexpression in hepatoma cells[ J ]. FEBS LETT, 2003, 545 (223) : 203-208.
21. Georgescu MM, Kirsch KH , KaloudisP , et al . Stabilization and productive positioning roles of the C2 domain of PTEN tumor suppressor [J ] . Cancer Res , 2000 , 60(24) :7033 -7038.
22. Vazquez F , Ramaswamy S , Nakamura N , et al . Phosphorylation of the PTEN tail re- gulates protein stability and function[J ] . Mol Cell Biol , 2000 , 20 (14) :5010 - 5018.
23. Das S , Dixon JE , Cho W. Membrane-binding and activation mechanism of PTEN [ J ] . Proc Natl Acad Sci USA , 2003 , 100 ( 13) :7491 - 7496.
24. Vazquez F , Grossman SR , Takahashi Y, et al . Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex [J ] . J Biol Chem , 2001 , 276 (52) :48627 - 48630.
25. Maehama T , Okahara F , Kanaho Y. The tumour suppressor PTEN: involvement of a tumour suppressor candidate protein in PTEN turnover[J ] . Biochem Soc Trans , 2004 , 32 (Pt2) :343 - 347.
26. Kotelevets L , van Hengel J , Bruyneel E. Implication of the MAGI1b/ PTEN signalosome in stabilization of adherens junctions and suppression of invasiveness[J ] . FASEB J , 2005 , 19 (1) :115 - 117.
27. Subauste MC , Nalbant P , Adamson ED , et al . Vinculin controls PTEN protein level by maintaining the interaction of the adherens junction protein beta-catenin with the scaffolding protein MAGI22[J ] . J Biol Chem , 2005 , 280 (7) :5676 - 5681.
28. Mahimainathan L , Choudhury GG. Inactivation of platelet-derived growth factor receptor by the tumor suppressor PTEN provides a novelmechanism of action of the phosphatase[J ] . J Biol Chem , 2004 , 279 (15) :15258 - 15268.
29. Cai XM, Tao BB , Wang LY, et al . Protein phosphatase activity of PTEN inhibited the invasion of glioma cells with epidermal growth factor receptor mutation type III expression[J ] . Int J Cancer , 2005 , 117(6) :905 - 912.
30. Sanchez T , Thangada S , Wu MT , et al . PTEN as an effector in the signaling of anti- migratory G protein-coupled receptor [J ] . Proc Natl Acad Sci USA , 2005 , 102 (12) :4312 - 4317.
31. Liu JL , Sheng X, Hortobagyi ZK, et al . Nuclear PTEN-mediated growth suppression is independent of Akt down2regulation [J ] . Mol Cell Biol , 2005 , 25 (14) :6211 - 6224.
32. Datta SR , Brunet A , Greenberg ME , et al . Cellular survival : a play in three Akts[J ] . Genes Dev , 1999 , 13(22) : 2905-2927.
33. Le Good JA , Ziegler WH , Parekh DB , et al . Protein kinase C isotypes controlled byphosphoinositide 3-kinase through the protein kinase PDK1 [ J ] . Science , 1998 ,281 (53 85) : 2042-2045.
34. Dutil EM , Toker A , Newton AC. Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK21) [J ] . Curr Biol , 1998 , 8(25) :1366-1375.
35. Parent CA , Blacklock BJ , Froehlich WM , et al . Gprotein signaling events are acti- vated at the leading edge of chemotactic cells[J ] . Cell , 1998 , 95 (1) : 81291.
36. Liu Q , Sasaki T , Kozieradzki I , et al . SHIP is a negative regulator of growth factor receptor-mediated PKB/Akt activation and myeloid cells survival[J ] . Genes Dev ,1999 , 13 (7) :786-791.
37. Pianetti S , Arsura M , Romieu Mourez R , et al . Her-2/neu overexpression induces NF-kappaB via a PI3-kinase/Akt pathway involving calpain2mediated degradation of IkappaB-alpha that can be inhibited by the tumor suppressor PTEN [ J ] . Oncogene , 2001 , 20 ( 11) : 1287-1299.
38. Yoganathan TN , Costello P , Chen X , et al . Integrin-linked kinase ( ILK) : a“hot”therapeutic target [ J ] .Biochem Pharmacol , 2000 , 60 (8) : 1115-1119.
39. Rodrigues GA , Falasca M , Zhang Z , et al . A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling [ J ] . Mol Cell Biol , 2000 , 20(14) : 1448-1459.
40. Stambolic V , MacPherson D , Sas D , et al . Regulation of PTEN transcription by p53[J ] . Mol Cell , 2001 , 8 (2) :317 - 325.
41. Freeman DJ , Li AG, Wei G, et al . PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms[J ] . Cancer Cell , 2003 , 3 (2) :117 - 130.
42. Mayo LD , Seo YR , Jackson MW, et al . Phosphorylation of human p53 at serine 46 determines promoter selection and whether apoptosis is attenuated or amplified [ J ] . J Biol Chem , 2005 , 280 ( 28) :25953 - 25959.
43. Ebert MP, fei G, Schandi L et al. Reduced PTEN expression in the pancreas over- expressing transforming growth factor-beta 1. Br J Cancer. 2002 Jan 21;86(2):257-62.
44. Latta E,Chapman WB. PTEN mutations and evolving concepts in endometrial neoplasia.Curr Opin Obstet Gynecol. 2002 Feb;14(1):59-65.
45. Waite K A , et al. BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels. Hum Mol Genet ,2003 , 12 (6) : 679
46. Wu W, et al. Zinc2induced PTEN protein degradation through the proteasome pathway in human airway epithelial cells. J Biol Chem , 2003 , 278 (30) : 28258
47. Han B, et al. Regulation of constitutive expression of mouse PTEN by the 5-untranslated region. Oncogene , 2003 , 22 (34) : 5325
48. Farrow B , et al. Activation of PPARgamma increases PTEN expression in pancreatic cancer cells. Biochem Biophys Res Commun ,2003 , 301 (1) : 50
49. Virolle T , et al. The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling. Nat Cell Biol , 2001 , 3(12) : 1124
50. Zhou B P , et al. HER-2/ neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol , 2001 , 3 (11) : 973
51. Fukuda R , Hayashi A ,Utsunomiya A , et al . Alteration of phosphatidylinositol 3- kinase cascade the mutilobulated nuclear formation of adult T-cell Leukemia lymphoma (ATLL) [ J ] . Proc Natl Acad Sci USA , 2005 , 102(42) :15213 - 15218.
52. Tabellini G, Cappellini A, Tazznri PL ,et al . Phosphoinositide 3-kinase/Akt invol- vement in arsenic trioxide resistance of human leukemia cells[J]. Cell Physiol,2005 ,202 (2) :623 - 634.
53. Zhou M, Gu L , Findley HW.PTEN reverses MDM2-mediated chemotherapy resistance by interacting with p53 in acute lymphoblastic leukemia cells[J]. Cancer Res ,2003, 63 (1 9) :6357 - 6362.
54. Suzuki A, de la Pompa JL, Stambolic V,et al . High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice[J ] . Curr Biol , 1998 ,8(21) :1169 - 1178.
55. Suzuki A ,Yamaguchi MT ,Ohteki T ,et al . T-cell specific loss of pten leads to defects in central and peripheral tolerance[J ] . Immunity ,2001 ,14 (5) :523 - 534.
56.黎岳南,冯德云,郑晖.非霍奇金淋巴瘤组织中PTEN蛋白和P27蛋白的表达[J ] .湖南医科大学学报,2003 ,28(3) :233 - 236.
57.孙宏伟,郑华川,吴东英,等. PTEN蛋白与Caspase-3表达在胃原发恶性淋巴瘤的意义[J] .肿瘤学杂志,2004 ,3(10) :159 - 161.
58. Ge NL , Rudikoff S. Expression of PTEN in PTEN-deficient multiple myeloma cells abolishes tumor growth in vivo [ J ] . Oncogene , 2000 , 19 (36) :4091 - 4095.
2. Lee JO , Yang H , Georgescu MM , et al .Crystal structure of the PTEN tumor suppressor :implications for its phosphoinositide phosphatase activity and membrane association . Cell , 1999 , 99 ( 3) :323-334.
3. Cantley LC , Neel BC. New insight into tumor suppression : PTEN suppresses tumor formation by restraining the phosphoinositide 32kinase/ AKT pathway. Proc Natl Acad Sci USA. 1999 , 96∶4240～4245.
4. Duerr, E. M., Rollbrocker, et al . PTEN mutations in gliomas and glioneuronal tumors. Oncogene, 16: 2259–2264, 1998.
5. Tsao, H. S., Zhang, X., et al .Identification of PTEN/MMAC 1 alterations in uncultured melanomas and melanoma cell lines. Oncogene, 16: 3397–3402, 1998.
6. Perren, A., Weng, L-P., Boag, et al .Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. Am. J. Pathol., 155:1254–1260, 1999.
7. Cairns, P., Okami, K., Halachmi, S., et al .Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res., 57: 4997–5000, 1997.
8. Mutter, G. L., Lin, et al .Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J. Natl. Cancer Inst. (Bethesda), 92: 924–930, 2000.
9. Kondo, K., Yao, M., Kobayashi, et al . PTEN/MMAC1/TEP1 mutations in human primary renal-cell carcinomas and renal carcinoma cell lines. Int. J. Cancer, 91: 219–224, 2001.
10. Martelli AM, Nyakern M, Tabellini G, et al. Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia. Leukemia 2006. 20: 911–928.
11. Xu Q, Simpson S. E,Scialla T. J, et al. Survival of acute myeloid leukemia cells requires PI3 kinase activation. Blood, 2003,102: 972–980.
12. Grandage V. L, Gale R. E, Linch D. C, et al. PI3-kinase/Akt is constitutively active inprimary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-ΚB, Mapkinase and p53 pathways. Leukemia ,2005, 19: 586–594.
13. Cheong JW, Eom JI, Maeng HY, et al. Phosphatase and tensin homologue phosphorylation in the C-terminal regulatory domain is frequently observed in acute myeloid leukaemia and associated with poor clinical outcome. Br J Haematol 2003. 122: 454–456.
14. Min YH, Cheong JW, Lee MH, et al. Elevated S-phase kinase-associated protein 2 protein expression in acute myelogenous leukemia: its association with constitutive phosphorylation of phosphatase and tensin homologue protein and poor prognosis. Clin Cancer Res 2004. 10: 5123–5130.
15. Zhang J, Grindley JC, Yin T, Jayasinghe S, He XC, Ross JT et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 2006. 441:518–522.
16. 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: 475–482.
17. Zhou M, Gu L, Findley HW, Jiang R, Woods WG. PTEN reverses MDM2-mediated chemotherapy resistance by interacting with p53 in acute lymphoblastic leukemia cells. Cancer Res 2003; 63:6357–6362.
1. Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science ,1997,275: 1943–1947.
2. Cantley LC , Neel BC. New insight into tumor suppression : PTEN suppresses tumor formation by restraining the phosphoinositide 32kinase/ AKT pathway. Proc Natl Acad Sci USA. 1999 , 96∶4240～4245.
3. Duerr, E. M., Rollbrocker, et al . PTEN mutations in gliomas and glioneuronal tumors. Oncogene, 16: 2259–2264, 1998.
4. Tsao, H. S., Zhang, X., et al .Identification of PTEN/MMAC 1 alterations in uncultured melanomas and melanoma cell lines. Oncogene, 16: 3397–3402, 1998.
5. Perren, A., Weng, L-P., Boag, et al .Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. Am. J. Pathol., 155: 1254–1260, 1999.
6. Cairns, P., Okami, K., Halachmi, S., et al .Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res., 57: 4997–5000, 1997.
7. Mutter, G. L., Lin, et al .Altered PTEN expression as a diagnostic marker for the earliest endometrial precancers. J. Natl. Cancer Inst. (Bethesda), 92: 924–930, 2000.
8. Kondo, K., Yao, M., Kobayashi, et al . PTEN/MMAC1/TEP1 mutations in human primary renal-cell carcinomas and renal carcinoma cell lines. Int. J. Cancer, 91: 219–224, 2001.
9.元云飞,李锦清,杨祖立,等.肿瘤相关基因过甲基化的研究进展[J].癌症,2002,21(11):1267-1277.
10. Jean-Charles Soria, Ho-Young Lee, Janet I. Lee, et al. Lack of PTEN Expression in Non-Small Cell Lung Cancer Could Be Related to Promoter Methylation. Clinical Cancer Research ,2002 May, 8(5): 1178–1184.
11. James G. hermans,Jeremy R.Graff,Barry D. Nelkin, et al. Methylation-specific PCR: A novel PCR assay for methylation status of CpG islands. PNAS,1996,93:9821-9826 Xu Q, Simpson S. E,Scialla T. J, et al. Survival of acute myeloid leukemia cellsrequires PI3 kinase activation. Blood, 2003,102: 972–980.
12. Grandage V. L, Gale R. E, Linch D. C, et al. PI3-kinase/Akt is constitutively active in primary acute myeloid leukaemia cells and regulates survival and chemoresistance via NF-ΚB, Mapkinase and p53 pathways. Leukemia ,2005, 19: 586–594.
13. Zhang J, Grindley JC, Yin T, Jayasinghe S, He XC, Ross JT et al. PTEN maintains
14. haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 2006. 441:518–522.
15. Yilmaz OH, Valdez R, Theisen BK, et al. PTEN dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 2006. 441: 475–482.
16. Whang YE, Wu X, Suzuki H, et al. Inactivation of the tumor suppressor PTEN/ MMAC1 in advanced human prostate cancer through loss of expression. Proc Natl Acad Sci USA 1998;95:5246–50.
17. Ajay Goel, Christian N. Arnold, Donna Niedzwiecki, et al. Frequent Inactivation of PTEN by Promoter Hypermethylation in Microsatellite Instability-High Sporadic Colorectal Cancers Cancer Reserch, 2004 May 1 (64):3014–3021
18. Brognard J, Clark A. S., Ni, Y., and Dennis P. A. Akt/protein kinase B is constitutively active in non-small cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. Cancer Res., 61: 3986–3997, 2001.
19. Kauffmann-Zeh, A., Rodriguez-Viciana, P., Ulrich, E., et al. Suppression of c-Myc-induced apoptosis by Ras signaling through PI3K and PKB. Nature (Lond.), 385: 544–548, 1997.
20. Khwaja, A., Rodriguez-Viciana, P., Wennstrom, S., et al. Matrix adhesion and ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J., 16: 2783–2793, 1997.
21. Chen, R. H., Su, Y. H., Chuang, R. L., and Chang. T. Y. Suppression of transforming growth factor-β-induced apoptosis through a phosphatidylinositol 3-kinase/ Akt - dependent pathway. Oncogene, 17:1959–1968, 1998.
1.张之南主编.血液病诊断及疗效标准,第二版.北京:科学出版社.1998
2.彭孝廉.CML的诊断和鉴别诊断.中国医刊,1999,34(9):5
3. Melo JV, The molecular biology of chronic myeloid leukemia, Leukemia, 1996, 10: 751
4. Melo JV, Gordon DE, Cross NCP, et al. The ABL-BCR fusion gene is expressedin chronic myeloid leukemia. Blood, 1993,81: 158
5. Cortes JE, Talpaz M, Beran M, et al. Philadelphia chromosome– negative chronic myelogenous leukemia with rearrangement of the breakpoint cluster region. Cancer, 1995, 75:464
6. Saglio G, Guerrasio A, Rosso C, et al. New type of Bcr/Abl junction in Philadelphia chromosome-positive chronic myelogenous leukemia. Blood 1990;76:1819–24.
7. Pane F, Frigeri F, Sindona M, et al. Neutrophilic-chronic myeloid leukemia: a distinct disease with a specific molecular marker (BCR/ABL with C3/A2 junction). Blood 1996;88:2410–14.
8. Martinez-Lopez J, Ayala R, Albizua Q. Typical chronic myelogenous leukemia with e19a2 BCR/ABL transcript. Report of two cases. Haematologica 2002;87:ELT35.
9. Ohsaka A, Hoshino S, Kobayashi M, Kudo H, Kawaguchi R. Blast crisis of Philadelphia chromosome-positive chronic myeloid leukaemia carrying micro-bcr breakpoint (e19a2 and e191a). British Journal of Haematology 2002;118:251-4.
10. Lee JJ, Kim HJ, Kim YJ, Lee S, Hwang JY. Imatinib induces a cytogenetic response in blast crisis or interferon failure chronic myeloid leukemia patients with e19a2 BCR- ABL transcripts. Leukemia 2004;18:1539-40.
11. Mondal BC, Majumdar S, Dasgupta UB, Chaudhuri U, Chakrabarti P, Bhattacharyya S. e19a2 BCR-ABL fusion transcript in typical chronic myeloid leukaemia: a report of two cases. Journal of Clinical Pathology 2006;59:1102-3.
12. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM. Efficacy and safety of an abl specific tyrosine kinase inhibitor as targeted therapy for chronic myeloid leukemia. New England Journal of Medicine 2001;344:1031–7.
13. Hughes TP, Morgan GJ, Martiat P, Goldman JM. Detection of residual leukemia after bone marrow transplant for chronic myeloid leukemia: role of polymerase chain reaction in predicting relapse. Blood 1991;77:874-8.
14. Sinclair PB, Nacheva EP, Leversha M, Telford N, Chang J, Reid A. Large deletions at the t(9;22) breakpoint are common and may identify a poor-prognosis subgroup of patients with chronic myeloid leukemia. Blood 2000;95:738-43.
15.全国白血病与再生障碍性贫血流行病学调查协作组.全国白血病发病情况调查.中国医学科学院学报,1992,14(1):12
16. Kantarjian HM, Talpaz M, O'Brien S, Smith TL, Giles FJ, Faderl S. Treatment of philadelphia chromosome-positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clinical Cancer Research 2002;8:2167-76.
1. Bostrom J, Cobbers JM,Wolter M , et al . Mutation of the PTEN (MMAC1) tumor suppressor gene in a subset of glioblastomas but not in meningiomas with loss of chromosome arm 10q. Science ,1997 ,275 :1943-1947.
2. Steck PA ,Pershous MA ,Jasser SA , et al . Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet ,1997 ,15 :356.
3. Li DM,Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res, 1997 , 57 :2124-2129.
4. Leslie NR,Gray A, Pass I,Aet al. Analysis of the cellular functions of PTEN using catalytic domain and C-terminal mutations: differential effects of C-terminal deletion on signalling pathways downstream of phosphoinositide 3-kinase. Biochem J. 2000 Mar 15;346 Pt 3:827-33.
5. Myers MP ,Stolarov JP ,Eng C , et al . P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci USA ,1997 , 94 : 9052-9057
6. Tolkacheva T,Chan AM. Inhibition of H-Ras transformation by the PTEN/MMAC1/ TEP1 tumor suppressor gene. Oncogene. 2000 Feb 3;19(5):680-9.
7. Iijima M, Huang YE , Luo HR et al . Novel mechanism of PTEN regulation by its phosphatidylinositol 4 ,5-bisphosphate binding motif is critical for chemotaxis[J ] . J Biol Chem , 2004 , 279 (16) :16606 -16613.
8. Lee JO , Yang H , Georgescu MM, et al . Crystal structure of the PTEN tumor suppressor : implications for its phosphoinositide phosphatase activity and membrane association[J ] . Cell , 1999 , 99 (3) :323 - 334.
9. Raftopoulou M, Etienne-Manneville S , Self A , et al . Regulation of cell migration by the C2 domain of the tumor suppressor PTEN[J ] . Science , 2004 , 303 (5661) :1179 - 1181.
10. Valiente M, Andres-Pons A , Gomar B , et al . Binding of PTEN to specific PDZdomains contributes to PTEN protein stability and phosphorylation by microtubule- associated serine/ threonine kinases[J ] . J Biol Chem , 2005 , 280 (32) :28936 - 28943.
11. Miller SJ , Lou DY, Seldin DC , et al . Direct identification of PTEN phosphorylation sites[J ] . FEBS Letters , 2002 , 528 :145 - 153.
12. Sumitomo M, Iwase A, Zheng R, et al. Synergy in tumor supp ression by direct inter- action of neutral endopep tidase with PTEN[ J ]. Cancer Cell, 2004, 5 (1) : 67-78.
13. Gao X, Neufeld Tp, Pan D. Drosophila PTEN regulates cell growth and proliferation through PI3K-dependent and -independent pathways.Dev Biol, 2000 May 15; 221 (2) :404-18.
14. Yokoyama Y, Wan X, Shinohara A, et al. Expression of PTEN and PTEN pseudogene in endometrial carcinoma. Int J Mol Med. 2000 Jul; 6 (1) :47-50.
15. Teng DH, Hu R, Lin H, et al. MMAC1/PTEN mutations in primary tumor specimens and tumor cell lines. Cancer Res, 1997 Dec 1;57(23):5221-5.
16. Steck PA, Pershouse MA, Jasser, et, al. Identification of a candidate tumor suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers [J ], Nat Genet, 1997,15 (4 ) :356 - 363
17. Furnari FB, Lin H, Huang H , et al . Growth suppression of glioma cells by PTEN re- quires a functional phosphatase catalytic domain.Proc Natl Acad Sci USA , 1997, 94:1247 9-12484.
18. Stocker H, AndjelkovicM, Oldham S, et al. Living with lethal PIP3 levels: viability of flies lacking PTEN restored by a pH domain mutation in AKT/PKB [ J ]. Science, 2002, 1295 (5562) : 2088-2091.
19. Robertson GP , Furnari FB ,Miele ME , et al . In vitro loss of heterozygosity targets the PTEN/MMAC1 gene in melanoma. Proc Natl Acad Sci USA ,1998 ,95 :9418-9423.
20. Kang-Park S, Lee YI, Lee YI, et al. PTEN modulates insulin-like growth factorⅡ( IGF-Ⅱ)-mediated signaling : the protein phosphatase activity of PTEN downregulates IGF-Ⅱexpression in hepatoma cells[ J ]. FEBS LETT, 2003, 545 (223) : 203-208.
21. Georgescu MM, Kirsch KH , KaloudisP , et al . Stabilization and productive positioning roles of the C2 domain of PTEN tumor suppressor [J ] . Cancer Res , 2000 , 60(24) :7033 -7038.
22. Vazquez F , Ramaswamy S , Nakamura N , et al . Phosphorylation of the PTEN tail re- gulates protein stability and function[J ] . Mol Cell Biol , 2000 , 20 (14) :5010 - 5018.
23. Das S , Dixon JE , Cho W. Membrane-binding and activation mechanism of PTEN [ J ] . Proc Natl Acad Sci USA , 2003 , 100 ( 13) :7491 - 7496.
24. Vazquez F , Grossman SR , Takahashi Y, et al . Phosphorylation of the PTEN tail acts as an inhibitory switch by preventing its recruitment into a protein complex [J ] . J Biol Chem , 2001 , 276 (52) :48627 - 48630.
25. Maehama T , Okahara F , Kanaho Y. The tumour suppressor PTEN: involvement of a tumour suppressor candidate protein in PTEN turnover[J ] . Biochem Soc Trans , 2004 , 32 (Pt2) :343 - 347.
26. Kotelevets L , van Hengel J , Bruyneel E. Implication of the MAGI1b/ PTEN signalosome in stabilization of adherens junctions and suppression of invasiveness[J ] . FASEB J , 2005 , 19 (1) :115 - 117.
27. Subauste MC , Nalbant P , Adamson ED , et al . Vinculin controls PTEN protein level by maintaining the interaction of the adherens junction protein beta-catenin with the scaffolding protein MAGI22[J ] . J Biol Chem , 2005 , 280 (7) :5676 - 5681.
28. Mahimainathan L , Choudhury GG. Inactivation of platelet-derived growth factor receptor by the tumor suppressor PTEN provides a novelmechanism of action of the phosphatase[J ] . J Biol Chem , 2004 , 279 (15) :15258 - 15268.
29. Cai XM, Tao BB , Wang LY, et al . Protein phosphatase activity of PTEN inhibited the invasion of glioma cells with epidermal growth factor receptor mutation type III expression[J ] . Int J Cancer , 2005 , 117(6) :905 - 912.
30. Sanchez T , Thangada S , Wu MT , et al . PTEN as an effector in the signaling of anti- migratory G protein-coupled receptor [J ] . Proc Natl Acad Sci USA , 2005 , 102 (12) :4312 - 4317.
31. Liu JL , Sheng X, Hortobagyi ZK, et al . Nuclear PTEN-mediated growth suppression is independent of Akt down2regulation [J ] . Mol Cell Biol , 2005 , 25 (14) :6211 - 6224.
32. Datta SR , Brunet A , Greenberg ME , et al . Cellular survival : a play in three Akts[J ] . Genes Dev , 1999 , 13(22) : 2905-2927.
33. Le Good JA , Ziegler WH , Parekh DB , et al . Protein kinase C isotypes controlled byphosphoinositide 3-kinase through the protein kinase PDK1 [ J ] . Science , 1998 ,281 (53 85) : 2042-2045.
34. Dutil EM , Toker A , Newton AC. Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK21) [J ] . Curr Biol , 1998 , 8(25) :1366-1375.
35. Parent CA , Blacklock BJ , Froehlich WM , et al . Gprotein signaling events are acti- vated at the leading edge of chemotactic cells[J ] . Cell , 1998 , 95 (1) : 81291.
36. Liu Q , Sasaki T , Kozieradzki I , et al . SHIP is a negative regulator of growth factor receptor-mediated PKB/Akt activation and myeloid cells survival[J ] . Genes Dev ,1999 , 13 (7) :786-791.
37. Pianetti S , Arsura M , Romieu Mourez R , et al . Her-2/neu overexpression induces NF-kappaB via a PI3-kinase/Akt pathway involving calpain2mediated degradation of IkappaB-alpha that can be inhibited by the tumor suppressor PTEN [ J ] . Oncogene , 2001 , 20 ( 11) : 1287-1299.
38. Yoganathan TN , Costello P , Chen X , et al . Integrin-linked kinase ( ILK) : a“hot”therapeutic target [ J ] .Biochem Pharmacol , 2000 , 60 (8) : 1115-1119.
39. Rodrigues GA , Falasca M , Zhang Z , et al . A novel positive feedback loop mediated by the docking protein Gab1 and phosphatidylinositol 3-kinase in epidermal growth factor receptor signaling [ J ] . Mol Cell Biol , 2000 , 20(14) : 1448-1459.
40. Stambolic V , MacPherson D , Sas D , et al . Regulation of PTEN transcription by p53[J ] . Mol Cell , 2001 , 8 (2) :317 - 325.
41. Freeman DJ , Li AG, Wei G, et al . PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms[J ] . Cancer Cell , 2003 , 3 (2) :117 - 130.
42. Mayo LD , Seo YR , Jackson MW, et al . Phosphorylation of human p53 at serine 46 determines promoter selection and whether apoptosis is attenuated or amplified [ J ] . J Biol Chem , 2005 , 280 ( 28) :25953 - 25959.
43. Ebert MP, fei G, Schandi L et al. Reduced PTEN expression in the pancreas over- expressing transforming growth factor-beta 1. Br J Cancer. 2002 Jan 21;86(2):257-62.
44. Latta E,Chapman WB. PTEN mutations and evolving concepts in endometrial neoplasia.Curr Opin Obstet Gynecol. 2002 Feb;14(1):59-65.
45. Waite K A , et al. BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels. Hum Mol Genet ,2003 , 12 (6) : 679
46. Wu W, et al. Zinc2induced PTEN protein degradation through the proteasome pathway in human airway epithelial cells. J Biol Chem , 2003 , 278 (30) : 28258
47. Han B, et al. Regulation of constitutive expression of mouse PTEN by the 5-untranslated region. Oncogene , 2003 , 22 (34) : 5325
48. Farrow B , et al. Activation of PPARgamma increases PTEN expression in pancreatic cancer cells. Biochem Biophys Res Commun ,2003 , 301 (1) : 50
49. Virolle T , et al. The Egr-1 transcription factor directly activates PTEN during irradiation-induced signalling. Nat Cell Biol , 2001 , 3(12) : 1124
50. Zhou B P , et al. HER-2/ neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat Cell Biol , 2001 , 3 (11) : 973
51. Fukuda R , Hayashi A ,Utsunomiya A , et al . Alteration of phosphatidylinositol 3- kinase cascade the mutilobulated nuclear formation of adult T-cell Leukemia lymphoma (ATLL) [ J ] . Proc Natl Acad Sci USA , 2005 , 102(42) :15213 - 15218.
52. Tabellini G, Cappellini A, Tazznri PL ,et al . Phosphoinositide 3-kinase/Akt invol- vement in arsenic trioxide resistance of human leukemia cells[J]. Cell Physiol,2005 ,202 (2) :623 - 634.
53. Zhou M, Gu L , Findley HW.PTEN reverses MDM2-mediated chemotherapy resistance by interacting with p53 in acute lymphoblastic leukemia cells[J]. Cancer Res ,2003, 63 (1 9) :6357 - 6362.
54. Suzuki A, de la Pompa JL, Stambolic V,et al . High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice[J ] . Curr Biol , 1998 ,8(21) :1169 - 1178.
55. Suzuki A ,Yamaguchi MT ,Ohteki T ,et al . T-cell specific loss of pten leads to defects in central and peripheral tolerance[J ] . Immunity ,2001 ,14 (5) :523 - 534.
56.黎岳南,冯德云,郑晖.非霍奇金淋巴瘤组织中PTEN蛋白和P27蛋白的表达[J ] .湖南医科大学学报,2003 ,28(3) :233 - 236.
57.孙宏伟,郑华川,吴东英,等. PTEN蛋白与Caspase-3表达在胃原发恶性淋巴瘤的意义[J] .肿瘤学杂志,2004 ,3(10) :159 - 161.
58. Ge NL , Rudikoff S. Expression of PTEN in PTEN-deficient multiple myeloma cells abolishes tumor growth in vivo [ J ] . Oncogene , 2000 , 19 (36) :4091 - 4095.