真性红细胞增多症JAK2基因突变的检测及其临床意义
摘要
目的:应用等位基因特异性PCR技术和基因测序技术研究真性红细胞增多症(PV)中JAK2 V617F基因突变的发生率及其临床意义。方法:①研究对象:将112例恶性血液疾病患者分为三组。20例PV患者为PV组,其中男13例、女7例,年龄36-66岁。20例原发性血小板增多症(ET)、6例特发性骨髓纤维化(IMF)共26例作为其他MPD组进行检测。66例其他恶性血液疾病列为对照组,包括31例急性髓系白血病(AML)、13例急性淋巴细胞白血病(ALL)、17例慢性粒细胞白血病(CML)、和5例慢性淋巴细胞白血病(CLL)。另将5名健康正常人作为正常对照。PV的诊断标准参照PVSG和WHO制定的标准。②基因组DNA的制备:抽取患者外周血5 ml,常规分离白细胞,用QIAamp DNA mini kit按说明提取白细胞基因组DNA。基因组DNA的终浓度为100-200μg/ml。③PCR引物设计和PCR扩增:根据JAK2 V617F突变所在的第12外显子共设计三条引物,即上游的外侧引物和特异引物两条、下游的一条通用引物。外侧引物扩增片断为364bp,作为内对照,其引物为5’-ATCTATAGTCATGCTGAAAGAGGAGAAAG-3’;特异引物扩增片断长度203 bp,该引物跨越JAK2 V617F(G→T)的突变位点,其3’端的倒数第三位碱基错配设计,以扩增具有JAK2 V617F突变的标本,该特异引物为5’-AGCATTTGGTTTTAAATTATGGAGTATATT-3’;下游的通用引物为5’-CTGAATAGTCCTACAGTGTTTTCAGTTTCA-3’。反应体系为10×缓冲液2.5μl,引物(20μmol/L)1.6μl (包括外侧引物和特异引物、下游通用引物),10mmol/L dNTPs 0.5μl, 25mmol/L MgCl_21.4μl, Taq DNA聚合酶0.25μl,DNA模板25 ng,加去离子水至终体积25μl。反应程序为:应用Touch-Down程序,94℃预变性5 min ,94℃变性30s,65-56℃退火40s,72℃延伸30s,10个循环;94℃变性30s,58℃退火40s,72oC延伸30s,33个循环;最后72℃延伸7 min。④琼脂糖凝胶电泳:产物经20 g/L琼脂糖凝胶电泳后紫外光透视仪分析图像并照相。⑤基因测序:对阳性标本和随机抽取的10例阴性标本,再次分别在与上述相同的反应体系和程序条件下,以外侧引物进行PCR反应。PCR扩增产物经过纯化后,由上海生工生物公司进行测序。将所得到的测序结果与野生型基因序列进行对比。⑥统计学处理:应用SPSS(10.0)统计软件包进行统计学分析。结果:①JAK2 V617F突变检测情况:等位基因特异性PCR检测发现JAK2 V617F突变阳性标本有203bp和364bp两条条带,而阴性标本只有一条364bp条带。20例PV中有14例存在JAK2 V617F突变(70.0%);40%的ET和33.3%IMF患者JAK2 V617F呈阳性。而AML、ALL、CML和CLL患者均未检测到JAK2 V617F突变现象。5例正常人也为阴性。PV组与对照组比较, P<0.001,而PV组与其他BCR/ABL阴性MPD组比较, P<0.05。②基因测序:等位基因特异性PCR检测所发现的阳性标本和所有的阴性标本进行基因测序。基因测序结果与等位基因特异性PCR检测相一致。③JAK2 V617F突变阳性与阴性PV的临床特征:将20例PV病例根据JAK2 V617F突变发生情况进一步分为JAK2 V617F阳性PV和JAK2 V617F阴性PV两个亚组。JAK2 V617F阳性组男10例、女4例,年龄36-66岁(平均57.6岁), Hb为179.0g/L-217.0 g/L (平均191.4 g/L) , WBC为5.9×10~9/L -22.6×109/L (平均13.2×10~9/L), BPC为153.0×10~9/L -787.0×10~9/L (平均297.5×109/L) ,Hct为51.0%-67.0%(平均59.1%)。JAK2 V617F阴性组男3例、女3例,年龄42-70岁(平均55.8岁),Hb为185.0g/L-225.0g/L (平均199.3 g/L), WBC为8.0×10~9/L -14.9×10~9/L (平均10.3×10~9/L) ,BPC为163.0×10~9/L- 246.0×10~9/L (平均209.7×10~9/L),Hct为56.0%-70.0%(平均61.7%)。JAK2 V617F阳性PV组脾肿大4例和肝肿大1例、阴性组脾肿大3例、无肝肿大病例,两组所有病例骨髓检查都是三系增生活跃。JAK2 V617F阳性和阴性病人的年龄、性别、外周血象、骨髓检查和肝脾肿大等临床生物学检查结果均无显著差异(两组比较均为P>0.05)。④JAK2 V617F阳性ET患者的Hb和WBC明显高于阴性患者,羟基脲的治疗效果较好,临床特征与PV患者相似;而JAK2 V617F阴性ET患者则以单纯BPC升高为主。结论:PV患者中JAK2 V617F突变高达70%(14/20例),高于其他MPD(ET和IMF)中的阳性率;而在AML、ALL、CLL、MDS等疾病中均阴性。因此,JAK2 V617F突变是PV患者的特征性标志,可以作为PV的诊断指标。JAK2 V617F阳性与阴性患者之间的临床生物学特征方面则无明显的差异。
Objective: To study the JAK2 V617F point mutation and its clinical significance by allele-specific polymerase chain reaction(AS-PCR) in combination with gene sequence analysis in polycythaemia vera (PV). Methods:①patients:PV group had 20 patients with PV;other group of myeloproliferative disorder(MPD) had 26 patients ,including 20 cases with essential thrombocythemia(ET) and 6 cases with idiopathial myelofibrosis(IMF).The control group had 66 patients, including 31 cases with acute myelogenous leukemia(AML),13 cases with acute lymphoblastic leukemia (ALL),17 cases with chronic myelogenous leukemia(CML);and 5 cases with chronic lymphocytic leukemia(CLL)。②Preparing genomic DNA: The white blood cell(WBC) were isolated from peripheral blood and preparing genomic DNA. The last concentration of genomic DNA was 100-200μg/ml。③PCR amplification:There were two upstream primers and one downstream. The lateral primer of upstream primer was 5’-ATCTATAGTCATGCTGAAAGAGGAGAAG-3’, which the PCR amplificative products including 364 bp fragment. The special primer of upstream primer was included 203 bp fragment (which primer was prepared by 617 codon of JAK2 gene,G→T,in exon 12).The universal downstream primer was 5’-CTGAATAGTCCTACAGTGTTTTCAGTTTCA-3’.The PCR responsive body included: 10×PCR buffer solution 2.5μl, primer(20μmol/L) 1.6μl (including two upstream and one downstream primer),10 mmol/LdNTPs 0.5μl, 25 mmol/L MgCl2 1.4μl, Taq DNA ploymerase 0.25μl,DNA 25 ng, added de-ion liquid to 50μl。The PCR responsive condition was included:predenaturation for 5min at 94℃, denaturation for 30s at 94℃, annealing for 40s at 60-65℃, extense for 30s at 72℃,10 circulations in all.Then, denaturation for 30s at 94℃, annealing for 40s at 58℃, extense for 30s at 72℃,33 circulations in all.At last, again extense for 7min at 72 oC.④Agarose gel electrophoresis:The purified PCR amplificative products were electrophorosed by 20g/L agarose gel, then, were photographied under ultraviolet light and analysed picture.⑤Gene sequence analysis:Both the positive and nagetive sample were sequenced after purified, and compared it with wide type JAK2 gene.⑥Statistical analysis: Compared PV patients with patients of ET and IMF, also compared PV group with control group by SPSS 10.0. Results:①JAK2 V617F gene mutation analysis:The cases of JAK2 V617F point mutation had two strands, which were 364 bp and 203 bp. But there was only one strand of 364 bp in negative cases of JAK2 V617F point mutation .The 14 cases of 20 PV patients (70.0%),8 cases of 20 ET patients(40.0%) and 2 cases of 8 IMF patients (33.3%) had the JAK2 V617F point mutation,but there was no JAK2 V617F point mutation in AML,ALL,CML and CLL. Compared PV group with control group, P<0.001,and Compared PV group with other MPD group(ET and IMF), P<0.05.②Gene sequence analysis:All positive and negative samples were sequenced, the results were the same as the results confirmed by AS-PCR.③The clinical and biological character: There were 10 males and 4 females in the positive group of JAK2 V617F PV patients, the age range was 36-66 years, Hb was 179.0-217.0 g/L, WBC was 5.9-22.0×10~9/L,BPC was 153.0-787.0×10~9/L, Hct was 55.0-67.0%. There were 3 males and 3 females in the negative group of JAK2 V617F PV patients,the age range was 42-70 years,Hb was 185.0-225.0 g/L,WBC was 8.0-14.9×10~9/L,BPC was 163.0-246.0×10~9/L, Hct was 56.0-70.0%. There were four and three splenomegaly patients respectively, in the positive and negative group of JAK2 V617F.And the two group patients’bone marrow were all active prolification. There were no difference between the positive patients of JAK2 V617F and the negative patients of JAK2 V617F in clinical and biological character including age, sex, Hb, WBC, BPC, bone marrow, and hepatomegaly and splenomegaly etc. (P>0.05).④The count of Hb and WBC of the JAK2 V617F positive ET patients were higher than the negative patients’,and the count of BPC of the JAK2 V617F negative ET patients was higher than the positive patients’. Conclusion :The positive rate of JAK2 V617F point mutation in PV patients was 70.0%(14/20), it was higher than the positive rate of JAK2 V617F in ET and IMF.But the JAK2 V617F was negative in all patients of AML, ALL, CML, and CLL. Thus, JAK2 V617F point mutation was characteristic marker of PV patients, and was diagnosis marker of PV. There were no difference between the positive patients of JAK2 V617F and the negative patients of JAK2 V617F in clinical and biological character.
Objective: To study the JAK2 V617F point mutation and its clinical significance by allele-specific polymerase chain reaction(AS-PCR) in combination with gene sequence analysis in polycythaemia vera (PV). Methods:①patients:PV group had 20 patients with PV;other group of myeloproliferative disorder(MPD) had 26 patients ,including 20 cases with essential thrombocythemia(ET) and 6 cases with idiopathial myelofibrosis(IMF).The control group had 66 patients, including 31 cases with acute myelogenous leukemia(AML),13 cases with acute lymphoblastic leukemia (ALL),17 cases with chronic myelogenous leukemia(CML);and 5 cases with chronic lymphocytic leukemia(CLL)。②Preparing genomic DNA: The white blood cell(WBC) were isolated from peripheral blood and preparing genomic DNA. The last concentration of genomic DNA was 100-200μg/ml。③PCR amplification:There were two upstream primers and one downstream. The lateral primer of upstream primer was 5’-ATCTATAGTCATGCTGAAAGAGGAGAAG-3’, which the PCR amplificative products including 364 bp fragment. The special primer of upstream primer was included 203 bp fragment (which primer was prepared by 617 codon of JAK2 gene,G→T,in exon 12).The universal downstream primer was 5’-CTGAATAGTCCTACAGTGTTTTCAGTTTCA-3’.The PCR responsive body included: 10×PCR buffer solution 2.5μl, primer(20μmol/L) 1.6μl (including two upstream and one downstream primer),10 mmol/LdNTPs 0.5μl, 25 mmol/L MgCl2 1.4μl, Taq DNA ploymerase 0.25μl,DNA 25 ng, added de-ion liquid to 50μl。The PCR responsive condition was included:predenaturation for 5min at 94℃, denaturation for 30s at 94℃, annealing for 40s at 60-65℃, extense for 30s at 72℃,10 circulations in all.Then, denaturation for 30s at 94℃, annealing for 40s at 58℃, extense for 30s at 72℃,33 circulations in all.At last, again extense for 7min at 72 oC.④Agarose gel electrophoresis:The purified PCR amplificative products were electrophorosed by 20g/L agarose gel, then, were photographied under ultraviolet light and analysed picture.⑤Gene sequence analysis:Both the positive and nagetive sample were sequenced after purified, and compared it with wide type JAK2 gene.⑥Statistical analysis: Compared PV patients with patients of ET and IMF, also compared PV group with control group by SPSS 10.0. Results:①JAK2 V617F gene mutation analysis:The cases of JAK2 V617F point mutation had two strands, which were 364 bp and 203 bp. But there was only one strand of 364 bp in negative cases of JAK2 V617F point mutation .The 14 cases of 20 PV patients (70.0%),8 cases of 20 ET patients(40.0%) and 2 cases of 8 IMF patients (33.3%) had the JAK2 V617F point mutation,but there was no JAK2 V617F point mutation in AML,ALL,CML and CLL. Compared PV group with control group, P<0.001,and Compared PV group with other MPD group(ET and IMF), P<0.05.②Gene sequence analysis:All positive and negative samples were sequenced, the results were the same as the results confirmed by AS-PCR.③The clinical and biological character: There were 10 males and 4 females in the positive group of JAK2 V617F PV patients, the age range was 36-66 years, Hb was 179.0-217.0 g/L, WBC was 5.9-22.0×10~9/L,BPC was 153.0-787.0×10~9/L, Hct was 55.0-67.0%. There were 3 males and 3 females in the negative group of JAK2 V617F PV patients,the age range was 42-70 years,Hb was 185.0-225.0 g/L,WBC was 8.0-14.9×10~9/L,BPC was 163.0-246.0×10~9/L, Hct was 56.0-70.0%. There were four and three splenomegaly patients respectively, in the positive and negative group of JAK2 V617F.And the two group patients’bone marrow were all active prolification. There were no difference between the positive patients of JAK2 V617F and the negative patients of JAK2 V617F in clinical and biological character including age, sex, Hb, WBC, BPC, bone marrow, and hepatomegaly and splenomegaly etc. (P>0.05).④The count of Hb and WBC of the JAK2 V617F positive ET patients were higher than the negative patients’,and the count of BPC of the JAK2 V617F negative ET patients was higher than the positive patients’. Conclusion :The positive rate of JAK2 V617F point mutation in PV patients was 70.0%(14/20), it was higher than the positive rate of JAK2 V617F in ET and IMF.But the JAK2 V617F was negative in all patients of AML, ALL, CML, and CLL. Thus, JAK2 V617F point mutation was characteristic marker of PV patients, and was diagnosis marker of PV. There were no difference between the positive patients of JAK2 V617F and the negative patients of JAK2 V617F in clinical and biological character.
引文
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41. Vardiman JW, Harris NL, Brunning RN: The World Health Organization(WHO) classipication of the myeloid neoplasms. Blood, 2002;100(7):2292-2302.
42. Spivak JL,Barosi G,Togrnoni G,et al.Chronic myeloprolificative disorders, Hematology, 2003 (Am Soc Hematol Educ Progrm);200-224.
43. Bench AJ,Heike LP.Chromosome abnormalities and molecular markers in myeloprolificative disorders,Smin Hematol,2005;42(4):196-205.
44. Pardanani A,Tefferi A.Imatinib targets other than bcr/abl and their clinical relevance in myeloid disdorers.Blood,2004;104(7):1931-1939.
45. Kralovics R,Teo SS,Buser AS.Altered gene expression in myeloprolificative disorders correlates with activation of signaling by the V617F mutation of JAK2.Blood,2005;106(10):3374-3375.
46. Mc Lornan DP,Percy MMJ,Jones AV,et al.Chronic neutrphilic leukemia with an associated V617F JAK2 tyrosine kinase mutation. Haematologica, 2005; 90(12):1696-1697.
47. Levine RL,Loriaux M,Huntly BJ,et al.The JAK2 V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia,but not in acute lymphoblastic leukemia or chronic myeloid leukemia.Blood, 2005; 106(10):3377-3379.
48. Scott LM,Campbell PJ,Baxter EJ,et al. The JAK2 V617F mitation is uncommon in cancers and in myeloid malignancies other than the classic myeloprolificative disorders.Blood,2005;106(8):2920-2921.
49. James C,Ugo V,Casadevall N,et al.A JAK2 mutation in myeloprolificativedisorders:pathogenesis and therapeutic and scientific prospects.Trends Mol Med,2005;11(12):546-554.
50. Walz C, Crowley BJ, Hudon HE, et al. Activated JAK2 with the V617F mutation promotes G1/S-phase transition.J Biol Chem. 2006,281(26): 18177-18183.
1. Dalal I,Arpaia E,Dadi H,et al.Cloning and characterization of the human homolog of mouse JAK2.Blood,1998;91(3):844-851.
2. Baxter EJ, Scott LM, Campbell PJ, et al.Acqurired mutation of the tyrosine kinase JAK2 in huamn myeloproliferative disorder.Lacent, 2005,365(9464):1054-1061.
3. Levine RL, Wadleigh M ,Cools J, et al.Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia,and myeloid metaplasia with myelofibrosis. Cancer Cell, 2005;7(4):387-397.
4. Kralovics R,Passamonti F,Buser AS,et al.A gain-of-function mutation of JAK2 in myeloproliferative disorders .N Eng J Med, 2005;352(17):1779-1790.
5. Saharinen P,Takaluoma K,Silvennoinen O.Regulation of the JAK2 tyrosine kinase by its pseudokinase domain.Mol Cell Biol,2000;20(10):3387-3395.
6. Feener EP,Rosario F,Dunn SL,et al.Tyrosine phosphorylation of JAK2 in the JH2 domain inhabits cytokine signaling.Mol Cell Biol, 2004;24(11):4968-4978.
7. Goerttler PS, Steimle C, Marz E, et al.The JAK2 V617F mutation,PRV-1 overexpression and EEC formation define a similar cohort of MPD patients.Blood,2005;106(8):2862-2864.
8. James C,Ugo V,Le Couedic JP,et al.A unique clonal JAK2 mutation leding to constitutive signaling causes polycythaemia vera.Nature, 2005;434(7037):1144-1148.
9. Zhao R,Xing S,Li Z,et al.Identification of an acquired JAK2 mutation in Polycythemia vera.J Biol Chem, 2005;280(24):22788-22792.
10. Campbell PJ,Green AR.The Myeloproliferative Disorders.N Engl J Med,2006;355(23): 2452-2456.
11. Levine RL, Loriaux M, Huntly BJP, et al. The JAK2 V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia,but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood, 2005;106(10):3377-3379.
12. Jelinek J,Oki Y,Gharibyan V,et al.JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia-chromosome negative CML and megakaryocytic leukemia. Blood, 2005;116(10):3370-3373.
13. Jones AV, Kreil S, Zoi K, et al.Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders.Blood, 2005;106(6):2162-2168.
14. Steensma DP,Dewald GW,Lasho TL,et al.The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both“atypical”myeloproliferative disorders and the myelodysplastic syndrome. Blood, 2005;106(4):1207-1209.
15. Huang LJ,Constantinescu SN,Lodish HF.The N-terminal domain of Janus kinase 2 is required for Golginprocessing and cell surface of erythropoietin receptor.Mol Cell.,2001;8(6):1327-1338.
16. Royer Y, Staerk J, Costuleanu M, et al. Janus kinases affect thrombopoietin receptor cell surface localization and stability.J Biol Chem ,2005;280(29):27251-27261.
17. Moliterno AR, Hankins WD, Spivak JL. Impaired expression of the thrombopoietin receptor by platelets from patients with polycythemia vera.N Engl Med.,1998,338(9): 572- 580.
18. Moliterno AR,Spivak JL.Posttranslational processing of the thrombopoietin receptor is impaired in polythemia vera.Blood.,1999;94(8):2555-2561.
19. Kralovics R,Guan Y,Prchal JT.Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera.Exp Hematol ,2002;30(3):229-236.
20. Roder S,steimle C,Meinhardt G,et al.STAT3 is constitutively active in some patients with polycythemia rubra vera .Exp Hematol, 2001;29(6):694-702.
21. Dai C, Chung IJ, Krantz SB. Increased erythropoiesis in polycythemia vera is associated with increased erythoid progenitor proliferation and increased phosphorylation of Akt/PKB.Exp Hematol, 2005;33(2):152-158.
22. Wadleigh M, DeAngelo DJ,Griffin JD,et al.After chronic myelogenous leukaemia : tyrosine kinase inhibitors in other hematologic malignancies.Blood, 2005;105(1):22-30.
23. Deininger MW, Goldman JM,Melo JV.The molecular biology of chronic myeloid leukemia.Blood, 2000;96(10):3343-3356.
24. Reilly JT. Receptor tyrosine kinase in normal and malignant haematopoiesis. Blood.,2003; 17(4):241 -248.
25. Ugo V, Marzac C, Teyssandier I,et al.Multiple signaling pathways are involved in erythropoietin- independent differentiation of erythroid progenitors in polythemia vera.Exp Hematol, 2004;32(2): 179-187.
26. Komura E,Chagraoui H,Mansat de Mas V, et al.Spontaneous STAT5 activation induces growth factor independence in idiopathic myelofibrosis: possible relationship with FKBP51 overexpression.Exp Hematol.,2003;31(7):622-630.
27. Witthuhn BA, Quelle FW, Silvennoinen O, et al. JAK2 associates with the erythropoitin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell ,1993; 74(2): 227-236.
28. Wu H, Liu X, Jaenisch R, et al. Generation of committed erythroid BFU-E and CFU-E progenitor dose not require erythropoietin or the erythropoietin receptor. Cell ,1995;83(1): 59-67.
29. Zeuner A,Pedini F,Signore M,et al.Increased death receptor resistance and FLIP short expression in polycythemia vera erythroid precursor cells. Blood, 2006;107(9):3459-3502.
30. Walz C,Crowley BJ,Hudon HE,et al.Activated JAK2 with the V617F mutation promotes G1/S-phase transition.J Biol Chem.2006;281(26):18177-18183.
31. Tefferi A, Lasho TL,Schwaqer SM,et al.The clinical phentype of wide, heterozygous,and homozygous JAK2 V617F in polycythemia vera. Cancer, 2006;106(3):631-635.
32. Cambpell PJ,Linda MS,Georgina B,et al.Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F status:a prospective study.Lancet,2005;366(9501):1945-1953.
33. Bench JA, Heike LP.Chromosome abnormalities and molecular markers in myeloproliferative disorders.Semin Hemato,2005;42(4):196-205.
34. Spivak JL.Polycythemia vera: Myths, mechanisms,and management.Blood,2002; 100(13): 4272-4292.
35. Pardnani A, Tefferi A.Imatinib targets other than bcr/abl and their clinical relevance in myeloid disorders. Blood,2004;104(7):1931-1939.
2. Osler W.Chronic cyanosis,with polycythemia and enlarged spleen:a new clinical entity.Am J Med Sci.1903;126:187.
3. Turk W.Beitrage zur kenntnis des symptomenbildes Polycythamie mit Milztumor and Zyanose.Wien Klin Wochenschr.1904;17:153.
4. Dameshek W.Some speculations on the myeloproliferative syndromes. Blood, 1951;6(4):372-375.
5. Prchal JF,Axelrad AA.Letter:bone marrow responses in polycythemia vera.N Eng J Med,1974;290(24):1382.
6. Dai CH, Krantz SB, Dessypris EN, et al. Polycythemia vera II: hypersensitivity of bone marrow erythroid, granulocyte-macrophage and megakaryocyte progenitor cell to interleukin-3 and granulocyte- macrophage colony-stimulating fator. Blood, 1992;80(4):891-899.
7. Li Y, Hetet G, Maurer A-M, et al. Spontaneous megakaryocyte colony formation in myeloproliferative disorders is not neutralizable by antibodies against IL3,IL6 and GM-CSF.Br J Haematol, 1994;87(3):471-476.
8. Kobayashi S, Teramura M,Hoshino S,et al.Circulating megakaryocyte progenitors in myeloproliferative disorders are hypersensitive to interleukin-3. Br J Haematol, 1993;83(3):539-544.
9. Axelrad AA, Eskinazi D, Correa PN, et al. Hypersensitivity of circulating progenitor cells to megakaryocyte growth and development fator (PEG-rHu MGDF) in essential thrombocythemia. Blood, 2000;96(10):3310-3321.
10. Hinshelwood S, Bench AJ, Green AR. Pathogenesis of polycythemia vera. Blood Rev, 1997;11(4):224-232.
11. Murphy S: Diagnostic criteria and prognosis in polycythemia vera and essential thrombocythemia.Semin Hematol, 1999;36(Suppl 2):9-13.
12. Vardiman JW, Harris NL, Brunning RN:The World Health Organization(WHO) classipication of the myeloid neoplasms. Blood, 2002;100(7):2292-2302.
13. Reilly JT. Receptor tyrosine kinase in normal and malignant haematopoiesis. Blood.,2003; 17(4):241 -248.
14. Wadleigh M,DeAngelo DJ,Griffin JD,et al.After chronic myelogenous leukaemia: tyrosine kinase inhibitors in other hematologic malignancies. Blood,2005;105(1):22-30.
15. Baxter EJ, Scott LM, Campbell PJ, et al.Acqurired mutation of the tyrosine kinase JAK2 in huamn myeloproliferative disorder.Lacent, 2005;365(9464): 1054-1061.
16. Levine RL, Wadleigh M ,Cools J, et al.Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell, 2005;7(4):387-397.
17. Kralovics R,Passamonti F,Buser AS,et al.A gain-of-function mutation of JAK2 in myeloproliferative disorders .N Eng J Med, 2005;352(17):1779-1790.
18. James C,Ugo V,Le Couedic JP,et al.A unique clonal JAK2 mutation leding to constitutive signaling causes polycythaemia vera.Nature, 2005;43(7037)4: 1144-1148.
19. Zhao R,Xing S,Li Z,et al.Identification of an acquired JAK2 mutation in Polycy-themia vera. J Biol Chem, 2005;280(24):22788-22792.
20.宋君红,李建勇,张苏江.骨髓增殖性疾病JAK2基因V617F点突变研究.中华血液学杂志,2006;27(9):632-633.
1. Spivak JL.The chronic myeloproliferative disoders:clonality and clinical heterogeneity. Semin Hematol.2004;41(2 suppl.3):1-5.
2. Prchal JT.Polycythemia vera and other primary polycythemias. Curr Opin Hematol, 2005;12(2):112-116.
3. Deininger MW, Goldman JM,Melo JV.The molecular biology of chronic myeloid leukemia.Blood, 2000;96(10):3343-3356.
4. Prchal JF, Prchal JT.Molecular basis for polycythemia. Curr.Opin.Hematol, 1999; 6(2):100-109.
5. Spivak JL.Polycythemia vera:myths, mechanisms, and management. Blood , 2002;100(13): 4272-4290.
6. James C,Ugo V,Le Couedic JP,et al.A unique clonal JAK2 mutation leding to constitutive signaling causes polycythaemia vera.Nature, 2005; 434(7037): 1144-1148.
7. Zhao R,Xing S,Li Z,et al.Identification of an acquired JAK2mutation in Polycythemia vera.J Biol Chem, 2005;280(24):22788-22792.
8. Levine RL, Wadleigh M ,Cools J, et al.Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia,and myeloid metaplasia with myelofibrosis. Cancer Cell, 2005;7(4):387-397.
9. Baxter EJ, Scott LM, Campbell PJ, et al.Acqurired mutation of the tyrosine kinase JAK2 in huamn myeloproliferative disorder.Lacent, 2005;365(9464): 1054-1061.
10. Kralovics R, Passamonti F, Buser AS,et al.A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Eng J Med, 2005; 352(17): 1779-1790.
11. Goerttler PS, Steimle C, Marz E, et al.The JAK2 V617F mutation,PRV-1 overexpression and EEC fornation define a similar cohort of MPD patients. Blood, 2005;106(8):2862-2864.
12. Jelinek J,Oki Y,Gharibyan V,et al.JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia-chromosome negative CML and megakaryocytic leukemia. Blood, 2005;116(10):3370-3373.
13. Jones AV, Kreil S, Zoi K, et al.Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders.Blood, 2005; 106(6): 2162-2168.
14.宋君红,李建勇,张苏江.骨髓增殖性疾病JAK2基因V617F点突变研究.中华血液学杂志,2006;27(9):632-633.
15. Murphy S. Diagnostic criteria and prognosis in polycythemia vera and essential thrombocythemia.Semin Hematol,1999;36(suppl 2):9-13.
16. Vardiman JW.Myelodysplastic syndromes,chronic myeloprolificative diseases, and myelodysplastic/ myeloprolificative diseases.Semin Diagn Pathol,2003; 20(3):154-179.
17. Ugo V, Marzac C, Teyssandier I,et al.Multiple signaling pathways are involved in erythropoietin- independent differentiation of erythroid progenitors in polythemia vera.Exp Hematol, 2004;32(2): 179-187.
18. Komura E,Chagraoui H,Mansat de Mas V, et al.Spontaneous STAT5 activation induces growth factor independence in idiopathic myelofibrosis: possible relationship with FKBP51 overexpression.Exp Hematol., 2003;31(7):622-630.
19. Westwood NB,Gruszka-West AM,Pearson CE,et al.The incidences of trisomy 8,trisomy 9 and D20S108 deletion in polycythaemia vera:Analysis of blood granulocytes using interphase fluorescence in situhybridization?Br J Haematol, 2000;110(4):839-846.
20. Najfeld V,Montella L,Scalise A,et al.Exploring polycythemia vera with FISH: additional cryptic 9p is the most frequent abnormality detected.Br J Hematol, 2002;119(2):558-566.
21. Kralovics R,Guan YL,Prchal JT.Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera.Exp Hematol,2002; 30(3): 229-236.
22. Kralovics R,Beser AS,Teo SS,et al.Comparison of molecular markers in a cohort of patients with chronic myeloproliferative disorders. Blood,2003;(5); 102:1869-1871.
23. Royer Y,Staerk J,Costuleanu M,et al.Janus kinases affect thrombopoietin receptor cell surface localization and stability.J Biol Chem,2005;280(29): 27251-27261.
24. Prchal JT.Pathogenetic mechanisms of polycythemia vera and congenital polycythemic disorders. Semin Hematol,2001; 38 (suppl 2):10-20.
25. Prchal JF,Adamson JW,Murphy S,et al.Polycythemia vera.The in vitro response of normal and abnormal stem cell lines to erythropoietin.J Clin Invest.1978; 61(4): 1044-1047.
26. Dai C-H,Krantz SB,Means RT,et al.Polycythemia vera blood burst-forming units-erythroid are hypersensitive to interleukin-3.J Clin Invest,1991;87(2): 391-396.
27. Dai C-H,Krantz SB,Green WF,et al.Polycythemia vera III:Burst-forming- erythroid (BFU-E) response to stem cell factor and c-kit receptor expression.Br J Haematol,1994;86(1):12-21.
28. Calin GA,Sevignani C,Dumitru CD,et al.Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers.Proc Natl Acad Sci USA.2004; 101(9): 2999-3004.
29. Klippel S,Strunck E,Temerinac S,et al.Quantification of PRV-1 mRNAdistinguishes polycythemia vera from secondary erythrocytosis.Blood. 2003;102(10):3569-3574.
30. Cilloni D,Carturant S,Gottardi E,et al.Usefulness of the quantitative assessment of PRV-1 gene expression for the diagnosis of polycythemia vera and essential thrombocythemia patients. Blood,2004;103(6):2428.
31. Klipple S,Pahl HL.Molecular markers for the diagnosis of Philadelphia chromosome negative myeloprolificative disorders.Pathol Biol.2004;52(5): 267-274.
32. Temerinac S,Klipple S,Strunck E,et al.Cloning of PRV-1,a noval member of the uPAR receptor superfamily,which is overexpressed in polycythemia ruba vera. Blood. 2000;95(8):2569-2576.
33. Teofili L,Martini M,Luongo M,et al.Overexpression of polycythemia ruba vera-1 gene in essential thrombocythemia.J Clin Oncol.2002;世界人民20(20):4249-4254.
34. Teofili L,Martini M,Guidi F,et al.The PRV-1 gene expression in essential thrombocythemia. Blood.2004;104(9):2995-2996.
35. Tefferi A, Lasho TL,Schwaqer SM,et al.The clinical phentype of wide, heterozygous,and homozygous JAK2 V617F in polycythemia vera. Cancer, 2006;106(3):631-635.
36. Cambpell PJ,Grenn AR.The Myeloproliferative Disorders.N Engl J Med, 2006; 355(23):2452-2456.
37. Harrison CN,Green AR.Essential thrombocythemia.Hematol Oncol Clin North Am,2003;17(5):1175-1190.
38. Cambpell PJ,Linda MS,Georgina B,et al.Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status:a prospective study.Lancet,2005;366(9501):1945-1953.
39. Antonioli E,GuglielmelliP,Pancrazzi A,et al.Clinical implications of the JAK2 V617F mutation in essential thrombocythemia.Leukemia,2005;19(10): 1847-1849.
40. Dameshek W.Some speculations on the myeloprilificative syndromes, Blood, 1951;6(4):372-375.
41. Vardiman JW, Harris NL, Brunning RN: The World Health Organization(WHO) classipication of the myeloid neoplasms. Blood, 2002;100(7):2292-2302.
42. Spivak JL,Barosi G,Togrnoni G,et al.Chronic myeloprolificative disorders, Hematology, 2003 (Am Soc Hematol Educ Progrm);200-224.
43. Bench AJ,Heike LP.Chromosome abnormalities and molecular markers in myeloprolificative disorders,Smin Hematol,2005;42(4):196-205.
44. Pardanani A,Tefferi A.Imatinib targets other than bcr/abl and their clinical relevance in myeloid disdorers.Blood,2004;104(7):1931-1939.
45. Kralovics R,Teo SS,Buser AS.Altered gene expression in myeloprolificative disorders correlates with activation of signaling by the V617F mutation of JAK2.Blood,2005;106(10):3374-3375.
46. Mc Lornan DP,Percy MMJ,Jones AV,et al.Chronic neutrphilic leukemia with an associated V617F JAK2 tyrosine kinase mutation. Haematologica, 2005; 90(12):1696-1697.
47. Levine RL,Loriaux M,Huntly BJ,et al.The JAK2 V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia,but not in acute lymphoblastic leukemia or chronic myeloid leukemia.Blood, 2005; 106(10):3377-3379.
48. Scott LM,Campbell PJ,Baxter EJ,et al. The JAK2 V617F mitation is uncommon in cancers and in myeloid malignancies other than the classic myeloprolificative disorders.Blood,2005;106(8):2920-2921.
49. James C,Ugo V,Casadevall N,et al.A JAK2 mutation in myeloprolificativedisorders:pathogenesis and therapeutic and scientific prospects.Trends Mol Med,2005;11(12):546-554.
50. Walz C, Crowley BJ, Hudon HE, et al. Activated JAK2 with the V617F mutation promotes G1/S-phase transition.J Biol Chem. 2006,281(26): 18177-18183.
1. Dalal I,Arpaia E,Dadi H,et al.Cloning and characterization of the human homolog of mouse JAK2.Blood,1998;91(3):844-851.
2. Baxter EJ, Scott LM, Campbell PJ, et al.Acqurired mutation of the tyrosine kinase JAK2 in huamn myeloproliferative disorder.Lacent, 2005,365(9464):1054-1061.
3. Levine RL, Wadleigh M ,Cools J, et al.Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia,and myeloid metaplasia with myelofibrosis. Cancer Cell, 2005;7(4):387-397.
4. Kralovics R,Passamonti F,Buser AS,et al.A gain-of-function mutation of JAK2 in myeloproliferative disorders .N Eng J Med, 2005;352(17):1779-1790.
5. Saharinen P,Takaluoma K,Silvennoinen O.Regulation of the JAK2 tyrosine kinase by its pseudokinase domain.Mol Cell Biol,2000;20(10):3387-3395.
6. Feener EP,Rosario F,Dunn SL,et al.Tyrosine phosphorylation of JAK2 in the JH2 domain inhabits cytokine signaling.Mol Cell Biol, 2004;24(11):4968-4978.
7. Goerttler PS, Steimle C, Marz E, et al.The JAK2 V617F mutation,PRV-1 overexpression and EEC formation define a similar cohort of MPD patients.Blood,2005;106(8):2862-2864.
8. James C,Ugo V,Le Couedic JP,et al.A unique clonal JAK2 mutation leding to constitutive signaling causes polycythaemia vera.Nature, 2005;434(7037):1144-1148.
9. Zhao R,Xing S,Li Z,et al.Identification of an acquired JAK2 mutation in Polycythemia vera.J Biol Chem, 2005;280(24):22788-22792.
10. Campbell PJ,Green AR.The Myeloproliferative Disorders.N Engl J Med,2006;355(23): 2452-2456.
11. Levine RL, Loriaux M, Huntly BJP, et al. The JAK2 V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia,but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. Blood, 2005;106(10):3377-3379.
12. Jelinek J,Oki Y,Gharibyan V,et al.JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia-chromosome negative CML and megakaryocytic leukemia. Blood, 2005;116(10):3370-3373.
13. Jones AV, Kreil S, Zoi K, et al.Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders.Blood, 2005;106(6):2162-2168.
14. Steensma DP,Dewald GW,Lasho TL,et al.The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both“atypical”myeloproliferative disorders and the myelodysplastic syndrome. Blood, 2005;106(4):1207-1209.
15. Huang LJ,Constantinescu SN,Lodish HF.The N-terminal domain of Janus kinase 2 is required for Golginprocessing and cell surface of erythropoietin receptor.Mol Cell.,2001;8(6):1327-1338.
16. Royer Y, Staerk J, Costuleanu M, et al. Janus kinases affect thrombopoietin receptor cell surface localization and stability.J Biol Chem ,2005;280(29):27251-27261.
17. Moliterno AR, Hankins WD, Spivak JL. Impaired expression of the thrombopoietin receptor by platelets from patients with polycythemia vera.N Engl Med.,1998,338(9): 572- 580.
18. Moliterno AR,Spivak JL.Posttranslational processing of the thrombopoietin receptor is impaired in polythemia vera.Blood.,1999;94(8):2555-2561.
19. Kralovics R,Guan Y,Prchal JT.Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera.Exp Hematol ,2002;30(3):229-236.
20. Roder S,steimle C,Meinhardt G,et al.STAT3 is constitutively active in some patients with polycythemia rubra vera .Exp Hematol, 2001;29(6):694-702.
21. Dai C, Chung IJ, Krantz SB. Increased erythropoiesis in polycythemia vera is associated with increased erythoid progenitor proliferation and increased phosphorylation of Akt/PKB.Exp Hematol, 2005;33(2):152-158.
22. Wadleigh M, DeAngelo DJ,Griffin JD,et al.After chronic myelogenous leukaemia : tyrosine kinase inhibitors in other hematologic malignancies.Blood, 2005;105(1):22-30.
23. Deininger MW, Goldman JM,Melo JV.The molecular biology of chronic myeloid leukemia.Blood, 2000;96(10):3343-3356.
24. Reilly JT. Receptor tyrosine kinase in normal and malignant haematopoiesis. Blood.,2003; 17(4):241 -248.
25. Ugo V, Marzac C, Teyssandier I,et al.Multiple signaling pathways are involved in erythropoietin- independent differentiation of erythroid progenitors in polythemia vera.Exp Hematol, 2004;32(2): 179-187.
26. Komura E,Chagraoui H,Mansat de Mas V, et al.Spontaneous STAT5 activation induces growth factor independence in idiopathic myelofibrosis: possible relationship with FKBP51 overexpression.Exp Hematol.,2003;31(7):622-630.
27. Witthuhn BA, Quelle FW, Silvennoinen O, et al. JAK2 associates with the erythropoitin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell ,1993; 74(2): 227-236.
28. Wu H, Liu X, Jaenisch R, et al. Generation of committed erythroid BFU-E and CFU-E progenitor dose not require erythropoietin or the erythropoietin receptor. Cell ,1995;83(1): 59-67.
29. Zeuner A,Pedini F,Signore M,et al.Increased death receptor resistance and FLIP short expression in polycythemia vera erythroid precursor cells. Blood, 2006;107(9):3459-3502.
30. Walz C,Crowley BJ,Hudon HE,et al.Activated JAK2 with the V617F mutation promotes G1/S-phase transition.J Biol Chem.2006;281(26):18177-18183.
31. Tefferi A, Lasho TL,Schwaqer SM,et al.The clinical phentype of wide, heterozygous,and homozygous JAK2 V617F in polycythemia vera. Cancer, 2006;106(3):631-635.
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