骨髓增殖性肿瘤JAK2及TET2基因突变分析及意义
|
摘要
2005年,国际上多个研究小组几乎同时报道,在骨髓增殖性肿瘤(myeloproliferative neoplasm, MPN)患者造血干/祖细胞水平存在的获得性,克隆性的Janus激酶2 (the j anus kinase 2, JAK2) V617F体细胞突变。随后,国内外学者对其进行了广泛的研究。据报道,JAK2 V617F存在于65%-97%的真性红细胞增多症(polycythemia vera, PV)及23%-60%的原发性血小板增多症(essential thrombocythemia, ET)和35%-64%的原发性骨髓纤维化(primary myelofibrosis, PMF)以及20%慢性中性粒细胞白血病(chronic neutrophil leukemia, CNL)患者中。随着JAK2 V617F突变在MPN发病中的逐渐认识,2008年世界卫生组织(the World Health Organization,WHO)对MPN提出了新的分类及诊断标准。在新的分类及诊断标准中,强调了JAK2 V617F突变等其他分子及细胞遗传学事件在MPN中的作用。然而,JAK2 V617F突变并不是MPN所特有,如在5%骨髓增生异常综合征(myelodysplastic syndrome, MDS)患者也存在。另外,单一的JAK2 V617F突变在临床上会引起不同的疾病亚型。JAK2 V617F阴性的MPN是如何发病的,是否存在其他的癌基因或抑癌基因事件促进MPN的发生或影响其表型,也不是很清楚,尚有待进一步研究。2008年,Delhommeau等率先报道,在MPN患者中存在一种新的潜在抑癌基因ten-eleven translocation 2 (TET2)的突变。随后的研究发现,TET2基因突变广泛存在于各型JAK2 V617F阳性或阴性的MPN、MDS、原发或继发的急性髓系白血病(acute myeloid leukemia, AML)中。TET2突变包括框移突变,无义突变和错义突变,发生在TET2基因的多个外显子及多个位点上,但以3号,11号外显子最多见。尽管对JAK2V617F突变有些研究报道,但关于MPN中TET2基因突变及其临床特征,目前国内尚未见相关报道。为此,本研究分析了MPN患者中JAK2 V617F和TET2基因的突变情况及其临床特征,TET2基因突变与JAK2 V617F突变对MPN患者表型的影响。
首先,抽取40例MPN患者的骨髓或外周血,并提取其细胞基因组DNA,采用等位基因特异性荧光实时定量PCR (polymerase chain reaction, PCR)方法分析JAK2 V617F突变。同时,对所有患者TET2基因进行PCR扩增。在此基础上,将通过琼脂糖凝胶电泳验证的PCR扩增产物进行DNA序列测定,测序结果与美国国家生物技术信息学中心(National Center for Biotechnology Information, NCBI)提供的DNA数据库进行同源性比较,分析TET2基因突变情况。最后,分析TET2基因突变的临床特征以及TET2基因突变与JAK2 V617F突变对患者表型的影响。
结果显示,40例MPN患者中,28例为JAK2 V617F突变阳性,占所检测患者的70%。其中,PV患者16例(占所检测PV患者的76.2%),ET患者7例(占所检测ET患者的53.8%),以及5例无法明确分型的MPN患者。JAK2 V617F突变型PV患者发病年龄高于野生型患者(P=0.020),JAK2 V617F突变型ET患者外周血白细胞计数高于野生型患者(P=0.026),但血小板数低于野生型患者(P=0.048)。40例MPN患者中,有4例存在TET2基因突变,占所检测患者的10%。其中,2例为PV患者,另2例为ET患者。在这4例患者中,TET2基因突变均发生TET2基因的第11号外显子,分别是位于TET2基因第5548位核苷酸的T突变为G,导致第1721位亮氨酸突变为色氨酸；位于TET2基因第5670位核苷酸的A突变为G,此突变使TET2的第1762位异亮氨酸突变为缬氨酸；位于TET2基因第6269位核苷酸的G突变为A,该突变为同义突变；位于TET2基因第6364位核苷酸的G突变为A,导致TET2第1993位精氨酸突变为为谷氨酰胺。4例TET2基因突变患者均存在JAK2 V617F突变。TET2突变型患者在发病年龄、性别、外周血白细胞数、红细胞数、血小板数以及血红蛋白浓度与野生型患者无显著性差异。
以上结果表明,JAK2 V617F突变存在于大部分MPN患者,且JAK2 V617F阳性与JAK2 V617F阴性患者临床特征存在一定差异。TET2基因突变仅存在于小部分MPN患者,主要发生于TET2基因的第11号外显子,可与JAK2 V617F突变同时存在。TET2基因突变与患者发病年龄、性别可能无关,也不影响患者的外周血血象。
JAK2 V617F mutation is an acquired, clonal mutation occurred in hematopoietic stem/progenitor cells from myeloproliferative neoplasm (MPN) patients, which is first simultaneously reported by several groups in 2005. Extensive investigations about JAK2 V617F mutation were performed subsequently around the world. JAK2 V617F mutation is found in 65%～97%,23%～60%,35%～64% and 20% of patients with polycythemia vera (PV)、essential thrombocythemia (ET) primary myelofibrosis (PMF) and chronic neutrophil leukemia (CNL), respectively. As the role of JAK2 V617F mutation in the pathogenesis of MPN is gradually known, the World Health Organization (WHO) brought new classification and diagnostic standards to MPN, which emphasizedq the importance of JAK2 V617F mutation and other molecular or cytogenetic incidents in MPN. However, JAK2 V617F not only occures in MPNs, but in 5% of myelodysplastic syndrome (MDS) patients. Additionally, it is still remained to figure out why a single mutation causes different phenotypes in clinic, and how JAK2 V617F-negative MPN arises. Whether there are any other unknown oncogenic or anti-oncogenic incidents promoting the pathogenesis or influencing the phenotypes in MPN is not known and to be resolved. In 2008, Delhommeau reported the recurrent mutations in ten-eleven translocation 2 (TET2) gene, a new potential tumor suppressor gene, in MPN patients. Presently, TET2 mutation is frequently found in JAK2 V617F -positive or -negetive MPNs, MDSs, de nove or secondary acute myeloid leukemia (AML). The main mutations include frame-shift, nonsense and missense mutations in multiple sites, especially in the 3th and 11th exons of TET2 gene. It is true that there are some researches about JAK2 V617F mutation, but little is known about the incidence and clinical features of TET2 gene mutation in Chinese MPN patients. Therefore, in our this work, the incidence and clinical characteristics of JAK2 V617F and TET2 gene mutation, the effct of TET2 and JAK2 V617F gene mutation on MPN patients were investagated.
Firstly, samples of peripheral blood or bone marrow from 40 Chinese MPN patients were collected, and the whole genomic DNAs were extracted. Subsequently, allele-specific fluorescent real-time quantitative PCR was carried out to test the JAK2 V617F mutation. Meanwhile, TET2 gene was amplified by PCR and sequenced directly. Sequencing results were compared with the human genome database provided by National Center for Biotechnology Information (NCBI) to analyse TET2 gene mutation. Finally, clinical features of TET2 gene mutation and the effct of TET2 and JAK2 V617F gene mutation on MPN patients were studied.
The results showed that JAK2 V617F mutation took place in 28 MPN patients, accounting for 70% of the total 40 patients. Among them, 16 cases were PV patients, accounting for 76.2% of PV patients tested,7 cases were ET patients, accounting for 53.8% of ET patients tested, and 5 cases were MPN patients who cann't be classified exactly. JAK2 V617F-positive PV patients had a higher occurrence age than JAK2 V617F-negative patiens(P=0.020); JAK2 V617F-positive ET patiens had a higher count of leukocytes(P=0.026) and lower platelets(P=0.048) than JAK2 V617F-negative patients. Meanwhile,4 cases (10%) of the MPN patients were found to have TET2 gene mutation, of whom two cases were PV patients, and the other two were ET patients. All the four mutations were located in the 11th exon of TET2 gene. The first mutation was located in the 5548th nucleotide where the base T was substituted by base G, which caused 1721th amino acid of leucine replaced by tryptophan; The second one was the 5670th base A changing into base G, leading to 1762th amino acid of isoleucine replaced by valine; The third one was the 6269th base G changing into base A, which was a synonymous mutation; The last one was the 6364th base G changing into base A, resulting in the 1993th amino acid of arginine replaced by glutamine. JAK2 V617F mutation occured in all the four patients with TET2 gene mutation. Statistics analysis showed that the age、sex、the count of leukocytes、erythrocytes and platelets、the concentration of hemoglobin between TET2-mutant and -wild type patiens were not significantly different.
From all above, it could be concluded that JAK2 V617F mutation occures in the most of MPN patients and there are some significant clinical differences between JAK2 V617F-positive and -negative patiens. But TET2 gene mutation only exists in a small fraction of MPN patients, which is mostly located in the 11th exon of TET2 gene. TET2 gene mutation can coexist with JAK2 V617F mutation in the same MPN patients. TET2 gene mutation seems to have nothing to do with the patient's age and sex, it also has no effects on the count of leukocytes、erythrocytes、platelets and the concentration of hemoglobin of MPN patients.
首先,抽取40例MPN患者的骨髓或外周血,并提取其细胞基因组DNA,采用等位基因特异性荧光实时定量PCR (polymerase chain reaction, PCR)方法分析JAK2 V617F突变。同时,对所有患者TET2基因进行PCR扩增。在此基础上,将通过琼脂糖凝胶电泳验证的PCR扩增产物进行DNA序列测定,测序结果与美国国家生物技术信息学中心(National Center for Biotechnology Information, NCBI)提供的DNA数据库进行同源性比较,分析TET2基因突变情况。最后,分析TET2基因突变的临床特征以及TET2基因突变与JAK2 V617F突变对患者表型的影响。
结果显示,40例MPN患者中,28例为JAK2 V617F突变阳性,占所检测患者的70%。其中,PV患者16例(占所检测PV患者的76.2%),ET患者7例(占所检测ET患者的53.8%),以及5例无法明确分型的MPN患者。JAK2 V617F突变型PV患者发病年龄高于野生型患者(P=0.020),JAK2 V617F突变型ET患者外周血白细胞计数高于野生型患者(P=0.026),但血小板数低于野生型患者(P=0.048)。40例MPN患者中,有4例存在TET2基因突变,占所检测患者的10%。其中,2例为PV患者,另2例为ET患者。在这4例患者中,TET2基因突变均发生TET2基因的第11号外显子,分别是位于TET2基因第5548位核苷酸的T突变为G,导致第1721位亮氨酸突变为色氨酸；位于TET2基因第5670位核苷酸的A突变为G,此突变使TET2的第1762位异亮氨酸突变为缬氨酸；位于TET2基因第6269位核苷酸的G突变为A,该突变为同义突变；位于TET2基因第6364位核苷酸的G突变为A,导致TET2第1993位精氨酸突变为为谷氨酰胺。4例TET2基因突变患者均存在JAK2 V617F突变。TET2突变型患者在发病年龄、性别、外周血白细胞数、红细胞数、血小板数以及血红蛋白浓度与野生型患者无显著性差异。
以上结果表明,JAK2 V617F突变存在于大部分MPN患者,且JAK2 V617F阳性与JAK2 V617F阴性患者临床特征存在一定差异。TET2基因突变仅存在于小部分MPN患者,主要发生于TET2基因的第11号外显子,可与JAK2 V617F突变同时存在。TET2基因突变与患者发病年龄、性别可能无关,也不影响患者的外周血血象。
JAK2 V617F mutation is an acquired, clonal mutation occurred in hematopoietic stem/progenitor cells from myeloproliferative neoplasm (MPN) patients, which is first simultaneously reported by several groups in 2005. Extensive investigations about JAK2 V617F mutation were performed subsequently around the world. JAK2 V617F mutation is found in 65%～97%,23%～60%,35%～64% and 20% of patients with polycythemia vera (PV)、essential thrombocythemia (ET) primary myelofibrosis (PMF) and chronic neutrophil leukemia (CNL), respectively. As the role of JAK2 V617F mutation in the pathogenesis of MPN is gradually known, the World Health Organization (WHO) brought new classification and diagnostic standards to MPN, which emphasizedq the importance of JAK2 V617F mutation and other molecular or cytogenetic incidents in MPN. However, JAK2 V617F not only occures in MPNs, but in 5% of myelodysplastic syndrome (MDS) patients. Additionally, it is still remained to figure out why a single mutation causes different phenotypes in clinic, and how JAK2 V617F-negative MPN arises. Whether there are any other unknown oncogenic or anti-oncogenic incidents promoting the pathogenesis or influencing the phenotypes in MPN is not known and to be resolved. In 2008, Delhommeau reported the recurrent mutations in ten-eleven translocation 2 (TET2) gene, a new potential tumor suppressor gene, in MPN patients. Presently, TET2 mutation is frequently found in JAK2 V617F -positive or -negetive MPNs, MDSs, de nove or secondary acute myeloid leukemia (AML). The main mutations include frame-shift, nonsense and missense mutations in multiple sites, especially in the 3th and 11th exons of TET2 gene. It is true that there are some researches about JAK2 V617F mutation, but little is known about the incidence and clinical features of TET2 gene mutation in Chinese MPN patients. Therefore, in our this work, the incidence and clinical characteristics of JAK2 V617F and TET2 gene mutation, the effct of TET2 and JAK2 V617F gene mutation on MPN patients were investagated.
Firstly, samples of peripheral blood or bone marrow from 40 Chinese MPN patients were collected, and the whole genomic DNAs were extracted. Subsequently, allele-specific fluorescent real-time quantitative PCR was carried out to test the JAK2 V617F mutation. Meanwhile, TET2 gene was amplified by PCR and sequenced directly. Sequencing results were compared with the human genome database provided by National Center for Biotechnology Information (NCBI) to analyse TET2 gene mutation. Finally, clinical features of TET2 gene mutation and the effct of TET2 and JAK2 V617F gene mutation on MPN patients were studied.
The results showed that JAK2 V617F mutation took place in 28 MPN patients, accounting for 70% of the total 40 patients. Among them, 16 cases were PV patients, accounting for 76.2% of PV patients tested,7 cases were ET patients, accounting for 53.8% of ET patients tested, and 5 cases were MPN patients who cann't be classified exactly. JAK2 V617F-positive PV patients had a higher occurrence age than JAK2 V617F-negative patiens(P=0.020); JAK2 V617F-positive ET patiens had a higher count of leukocytes(P=0.026) and lower platelets(P=0.048) than JAK2 V617F-negative patients. Meanwhile,4 cases (10%) of the MPN patients were found to have TET2 gene mutation, of whom two cases were PV patients, and the other two were ET patients. All the four mutations were located in the 11th exon of TET2 gene. The first mutation was located in the 5548th nucleotide where the base T was substituted by base G, which caused 1721th amino acid of leucine replaced by tryptophan; The second one was the 5670th base A changing into base G, leading to 1762th amino acid of isoleucine replaced by valine; The third one was the 6269th base G changing into base A, which was a synonymous mutation; The last one was the 6364th base G changing into base A, resulting in the 1993th amino acid of arginine replaced by glutamine. JAK2 V617F mutation occured in all the four patients with TET2 gene mutation. Statistics analysis showed that the age、sex、the count of leukocytes、erythrocytes and platelets、the concentration of hemoglobin between TET2-mutant and -wild type patiens were not significantly different.
From all above, it could be concluded that JAK2 V617F mutation occures in the most of MPN patients and there are some significant clinical differences between JAK2 V617F-positive and -negative patiens. But TET2 gene mutation only exists in a small fraction of MPN patients, which is mostly located in the 11th exon of TET2 gene. TET2 gene mutation can coexist with JAK2 V617F mutation in the same MPN patients. TET2 gene mutation seems to have nothing to do with the patient's age and sex, it also has no effects on the count of leukocytes、erythrocytes、platelets and the concentration of hemoglobin of MPN patients.
引文
[1]Dameshek W. Some speculations on the myeloproliferative syndromes. Blood. 1951;6(4):372-375
[2]Martha Wadleigh,Ayalew Tefferi.Classification and diagnosis of myeloprolife-rative neoplasms according to the 2008 World Health Organization criteria.Int J Hematol.2010;91(2):174-179
[3]Runxiang Zhao, Shu Xing, Zhe Li,et al. The Japanese Society of Hematology 2010 Identification of an Acquired JAK2 Mutation in Polycythemia Vera.The Journal Of Biological Chemistry.2005; 280(24):22788-22792
[4]E Joanna Baxter,Linda M Scott,Peter J Campbell,et al. Acquired mutation of the tyrosine kinase JAK2 in human mycloproliferative disorders.The Lancet. 2005;365(9464):1054-1061
[5]Chloe James,Valeris Ugo,Jean-Pierre Le Couedic,et al.A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.Nature. 2005;434(67):1144-1148
[6]SJ Baker, SG Rane, EP Reddy. Hematopoietic cytokine receptor signaling. Oncogene.2007;26:6724-6737
[7]Reuther Gary W. JAK2 activation in myeloproliferative neoplasms:A potential role for heterodimeric receptors. Landes Bioscience.2008;7(6):714-719
[8]吴迪炯,孙洁,周郁鸿.骨髓增殖性疾病的认知和治疗.国陆军输血及血液学杂志,2010；33(3)：276-279
[9]顾树程,常春康.JAK2V617F在骨髓增殖性肿瘤中的研究进展.现代中西医结合杂志,2010；19(6)：769-771
[10]O kilpivaara, RL Levine. JAK2 and MPL mutations in myeloproliferative neoplasms:discovery and science. Leukemia,2008;22:1813-1817
[11]A Tefferi. The history of myeloproliferative disorders:before and after Dameshek. Leukemia,2008;22:3-13
[12]Ayalew Tefferi, D Gary Gilliand. Oncogenes in myeloproliferative Disorders. Landes Bioscience,2007;5:550-566
[13]David P, Steensma,Gordon W,et al.The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and myelodysplastic syndromes.Blood.2005; 106(4):1207-1209
[14]Frohling S,Lipka DB,Kayser S,et al.Rare occurrence of the JAK2V617F mutation in AML subtypes M5,M6,and M7.Blood,2006; 107:1242-1243
[15]Peter J,Campbell E,Joanna Baxter,et al.Mutation of JAK2 in the myeloproliferative disorders:timing,clonality studies,cytogenetic associations, and role in leukemic transformation.Blood.2006;108(10):3548-3555
[16]Alexandre Theocharides,Marjorie Boissinot,Francois Girodon,et al.Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation. Blood.2007; 110(1):375-379
[17]DelhommeauF,DupontS,JamesC,etal.TET2 isa noveltumor suppressor gene inac-tivated in myeloproliferative neoplasms:identification of a Pre-JAK2 V617F event. ASH Annual Meeting Abstracts 2008; 112:lba-3
[18]Omar Abdel-Wahab,Ann Mullally,Cyrus Hedvat,et al.Genetic characterization of TET1,TET2,and TET3 alterations in myeloid malignancies.Blood.2009; 114(1):144-147
[19]Olivier Kosmider,Veronique Gelsi-Boyer,Meyling Cheok,et al.TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs).Blood.2009;114(15):3285-3291
[20]Sabina I,Swierczek,Donghoon Yoon,et al.Extent of hematopoietic involvement by TET2 mutations in JAK2V617F polycythemia vera.Haematologica.2010; 96(5):775-778
[21]Olivier Kosmider, Veronique Gelsi-Boyer, Marion Ciudad, et al. TET2 gene mutation is a frequent and adverse event in chronic myelomonocytic leukemia. haematologica,2009;94(12):1676-1681
[22]Olivier Kosmider, Eric Delabesse, Veronique Mansat-deMas, et al. TET2 mutations in secondary acute myeloid leukemias:a French retrospective study. Haematologica,2011 Apr 20. [Epub ahead of print]
[23]A Tefferi,RL Levine,K-H Lim,et al. Frequent TET2 mutations in systemic mastocytosis:clinical,KITD816V and FIP1L1-PDGFRA correlaties.Leukemia. 2009;23(5):900-904
[24]Franz X.Schaub,Renate Looser,et al.Clonal analysis of TET2 and JAK2 mutations suggests that TET2 can be a late event in the progression of myeloproliferative neoplasms.Blood.2010; 115(10):2003-2007
[25]Saskia M C Langemeijer,Roland P Kuiper,Marieke Berends,et al.Acquired mutations in TET2 are common in myelodysplastic syndromes.Nature Gene-tics.2009;41(7):838-843
[26]A Tefferi,Apardanai,K-H Lim,et al.TET2 mutations and their clinical correla-tes in polycythemia vera,essential thrombocythemia and myelofibrosis. Leuke-mia.2009;23(5):905-911
[27]A Tefferi, K-H Lim, O Abdel-Wahab, et al. Detection of mutant TET2 in myeloid malignancies other than myeloproliferative meoplasms:CMML, MDS, MDS/MPN and AML.Leukemia.2009;23(7):1343-1345
[28]Delhommeau F, Dupont S, Della Valle V,et al.Mutation in TET2 in Myeloid Cancers. The New England Journal of Medicine.2009;360(22):2289-2301
[29]Campbell PJ,Griesshammer M,Dohner K,et al. V617F mutation in JAK2 is associated with poorer survival in idiopathic myelofibrosis. Blood,2005; 107(5): 2098-2100
[30]Mc Clure R, Mai M, Lasho T, et al. Validation of two clinically useful assays for evalution of JAK2-V617F mutation in chronic myeloproliferative disorders. Leukemia,2006;20(1):168-171
[31]袁利亚,李红,陈国安,等JAK2 V617F基因突变在骨髓增生性疾病中的发生率及其临床意义.浙江大学学报(医学版),2010；39(2)：202-206
[32]张苏江,李伟达,宋君红,等.等位基因特异性聚合酶链反应结合测序对骨髓增殖性疾病JAK2 V617F点突变的研究。中华医学杂志,2007；87(30)：2109-2112
[33]Tefferi A. JAK2 mutations and clinical practice in myeloproliferative neoplasms. Cancer J,2007; 13:366-371
[34]Panani AD. Janus kinase 2 mutations in Philadelphia negative chronic myeloproliferative disorders:Clinical implications. Cancer Lett,2009; 284(1):7-14
[35]张心菊,顾小叶,刘双春,等.采用荧光定量PCR检测JAK2基因V617F突变.中华检验医学杂志,2009；32(5)：583-586
[36]Morgani KJ,Gilliland DG.A role for JAK2 mutations in myeloproliferative diseases.Ann Rev Med,2008;59:213-222
[37]刘红星,童春容,蔡鹏,等.多重位点特异性PCR检测骨髓增殖性疾病五种JAK2基因突变。中华检验医学杂志,2009；32(1)：30-34
[38]晁红颖,沈益民,张日,等.135例骨髓增殖性肿瘤患者JAK2基因突变的定量研究.中华血液学杂志,2009；30(5)：321-325
[39]Ana Maria Vladareanu,Carsten Mullen-Tidow,Horia Bumbea, et al. Molecular markers guide diagnosis and treatment in Philadelphia chromosome-negative myeloproliferative disorders. Oncology Reports,2010; 23(3):595-604
[40]Jeffery M,Klco,PhD,et al.Molecular Pathology of Myeloproliferative neopl-asm.AM J Clin Pathol,2010;133(4):602-615
[41]A Tefferi, JW Vardiman. Classification and diagnosis of myeloproliferative neoplasms:the 2008 World Health Organization criteria and point-of-care diagnostic algorithms.leukemia,2008;22(1):14-22
[42]林凤茹,郭晓楠.WHO关于慢性骨髓增殖性疾病的分类和诊断标准.临床荟萃,2004；9(9)：539-540
[43]Jones AV,Silver RT,Waghorn K,Curtis C,Kreil S,Zoi K et al.Minimal molecular response in polycythemia vera patients treated with imatinib or interferon alpha.Blood 2006;107(8):3339-3341
[44]Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood,2008; 112(8):2065-3072
[45]Passamonti F,Rumi E,Pietra D,et al.Relation betweenJAK2(V617F) mutation status,granulocyte activation,and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders. Blood,2005; 107(9):3676-3682
[46]Barosi G,Bergamaschi G,Marchetti M,et al.JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis.Blood,2007;110(12):4030-4036
[47]A M Vannucchi,E Antonioli,P Guglielmelli,et al.Clinical correlates of JAK2-V617F presence or allele burden in myeloproliferative neoplasms:a critical reappraisal. Leukemia,2008; 22(7),:1299-1307
[48]Torsten Haferlach, Ulrike Bacher, Wolfgang Kern. The diagnosis of BCR/ABL-negative chronic myeloproliferative diseases (CMPD):a comprehe-nsive approach based on morphology, cytogenetics, and molecular markers. Ann Hematol,2008;87(1):1-10
[49]Ross L.Mechanisms of mutations in myeloproliferative neoplasms.Clinical Haematology,2009;22(4):489-494
[50]50Ross L,Levine,Claude Belisle,et al.X-inactivation-based clonality analysis and quantitative JAK2V617F assessment reveal a strong association between clonality and JAK2V617F in PV but not ET/MMM,and identifies a subset of JAK2V617F-negative ET and MMM patients with clonal hematopoiesis. Blood,2006;107(10):4139-4141
[51]Gurunathan Murugesan,Samer Aboudola,Hadrian Szpurka.Identification of the JAK2V617F mutation in chronic myeloproliferative disorders using FRET probes and melting curve analysis.Am J Clin Pathol,2006(4); 125:625-633
[52]Villeval JL,James C,Pisani DF,et al.New insights into the pathogenesis of JAK2 V617F-positive myeloproliferative disorders and consequences for the management of patients. Semin Thromb Hemost,2006;32(4Pt):341-351
[53]Lacout C, Pisani DF, Tulliez M, etal. JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary mylopibrosis. Blood,2006; 108:1652-1660
[54]Tefferi A,Lasho TL,Schwager SM,et al.The clinical phenotype of wild-type,heterozygous,and homozygous JAK2V617F in polycythemia vera. Cancer, 2006;106(3):631-635
[55]Campbell PJ,Scott LM,Buck G,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
[56]刘红星,童春荣,蔡鹏,等。真性红细胞增多症和原发性血小板增多症JAK2V617F基因纯合突变克隆分析。首都医科大学学报2008；29：113-117
[57]Tefferi A, Lasho TL, Schwaqer SM,et al. The clinical phenotype of wild type, heterozygous,and homozygous JAK2V617F in polycythemia vera. Cancer,2006; 106(3):631
[58]楼瑾,李玉珠,杜新,等。JAK2 V617F点突变在真性红细胞增多症中的诊断价值.岭南急诊医学杂志,2010；15(3)：176-177
[59]Fabian Mohr,K onstanze Dohner,Christian Buske,et al.TET Genes:new players in DNA demethylation ad important determinants for sternness. Experimental Hematology,2011;39(3):272-281
[60]SMC Langemeijer,JH Jansen,J Hooijer,et al.TET2 mutations in childhood leukemia.Leukemia,2011;25(1):189-192
[61]Bellanne-Chantelot C, Chaumarel I, Labopin M, et al. Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders.blood,2006; 108:346-352
[62]Omar Abdel-wahab, Taghi Manshouri, Jaypatel, et al. Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias.Cancer Res,2010;70(2):447-452
[1]苗振静,马旭辉。颅内恶性肿瘤发病机制研究进展.实用医药杂志,2010；27(2)：173-176
[2]唐颖.甲状腺癌相关基因研究进展.诊断病理学杂志,2010；17(5)：386-389.
[3]程广保,保璟霞.乳腺癌发病的基因调控机制.现代肿瘤医学,2010；18(9)：1848-1852
[4]周健.肝门胆管癌的基因组学.检验医学与临床,2010；7(18)：2021-2023.
[5]吕强,邢沈阳,赵志辉,等.结肠癌的研究现状及展望.中国实验诊断学,2009；13(8)：1134-1136
[6]翟洪顺,邹德学,聂李平,等.微分化急性髓系白血病病人MICM特征分析.现代医学仪器与应用,2008；2：4-10
[7]李正发,沈晓梅,王云娟,等.白血病MICM分开的临床和实验研究.昆明医学院学报,2001；1：9-13
[8]Ayton PM,Cleary ML.Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins.Oncogene 2001;20(40):5695-5707
[9]Lorsbach RB,M oore J,Mathew S,et al.tetl,a member of a novel protein family,is fused to MLL in acute myeloid leukemia containing the t(10;11) (q22;q23). Leukemia,2003; 17(3):637-641
[10]F Viguie,A Aboura,D Bouscary,et al.Common 4q24 deletion in four cases of hematopoietic malignancy:early stem cell involvement?Leukemia,2005; 19(8): 1411-1415
[11]Delhommeau F,Dupont S,James C,et al.Tet2 is a novel turn or suppressor gene inactivated in myeloproliferative neoplasms identification of a pre- JAK2 V617F event.ASH Annu Meet Abstr,2008;112:Iba-3
[12]Saskia M C Langemeijer,Roland P Kuiper,Marieke Berends,et al.Acquired mutations in TET2 are common in myelodysplastic syndromes. Nature Genetics, 2009;41(7):838-842
[13]Fabian Mohr,Konstanze Dohner,Christian Buske,et al.TET Genes:new players in DNA demethylation and important determinants for stemness.Experimental Hematology,2011;39(3):272-281
[14]A Tefferi,K-H Lim,O Abdel-Wahab,et al.Detection of mutant TET2 in myeloid malignancies other than myeloproliferative meoplasm:CMML,MDS, MDS/ MPN and AML.Leukemia.2009;23(7):1343-1345
[15]Delhommeau F, Dupont S, Della Valle V,et al.Mutation in TET2 in Myeloid Cancers. The New England Journal of Medicine.2009;360(22):2289-2301
[16]Baker, SG Rane, EP Reddy.hematopoietic cytokine receptor signaling. Oncogene, 2007;26,6724-6737
[17]Jeffery M Klco,Ravi Vij,Friederike H Kreisel,et al.Molecular Pathology of Myeloproliferative Neoplasms.Am J Clin Pathol 2010; 133:602-615
[18]Ross L Levine.Mechanisms of mutations in myeloproliferative neoplasms. Clinical Haematology,2009;22(4):489-494
[19]Scott LM,Tong W,Levine RL,et al.JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis.N Engl J Med,2007;356:459-468
[20]Pardanani AD,Levine RL,Lasho T,et al.MPL515 mutations in myeloproliferative and other myeloid disorders:a study of 1182 patients.Blood,2006; 108:3472-3476
[21]Pikman Y,Lee BH,Mercher T,et al.MPL W515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.PLoS Med,2006;3:e270
[22]Tefferi A, Thiele J, Orazi A, et al. Proposals and rationale for revision of the world Health Organization diagnostic criteria for polycythemia vera,essential thrombocythemia,and primary myelofibrosis:recommendations from an ad hoc international expert panel. Blood,2007; 110:1092-1097
[23]Tefferi,A Pardanani,K-H Lim,et al.TET2 mutations and their clinical correlates in polycythemia vera,essential thrombocythemia and myelofibrosis. leukemia, 2009;23(5):905-911
[24]Omar Abdel-Wahab,Ann Mullally,Cyrus Hedvat,et al.Genetic characterization of TET1,TET2,and TET3 alterations in myeloid malignancies. Blood.2009;114: 144-147
[25]Franz X.Schaub,Renate Looser,et al.Clonal analysis of TET2 and JAK2 mutations suggests that TET2 can be a late event in the progression of myeloproliferative neoplasms.Blood.2010; 115:2003-2007
[26]Omar Abdel-wahab, Taghi Manshouri, Jaypatel, et al. Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias.Cancer Res,2010;70:447-452
[27]Sabina I,Swierczek,Donghoon Yoon,et al.Extent of hematopoietic involvement by TET2 mutations in JAK2V617F polycythemia vera.Haematologica.2010; 96(5):775-778
[28]Dicker F, Haferlach C, Kern W, et al. RUNX1 mutations play a major role in the progression of MDS to sAML following MDS:a genetic and cytogenetic snalysis of sequential samples. Blood,2008;112:3634
[29]Pedersen-Bjergaard J, Pedersen M, Roulston D, et al. Different genetic pathways in leukemogenesis for patients presenting with therapy-related myelodysplasia and therapy-related acute myeloid leukemia. Blood,1995; 86(9); 3542-3552
[30]List AF, Vardiman J, Issa JP, et al. Myelodysplastic syndromes. Hematology Am Sco Hemtol Educ Program,2004; 297-317
[31]Hasse D, Germing U, Schanz j, et al. Insights into the prognostic impact of the karyotype in MDS and correlation with subtypes evidence from a core dataset of 124 patients. Blood,2007;110(13):4385-4395
[32]Nolte F, Hofmann WK. Myelodysplastic syndromes molecular pathogenesis and genomic changes. Ann Hematol,2008;87(10):777-795
[33]Ebert BL, Pretzl J, Bosco J, et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature,2008;451(7176):335-339
[34]Pellagatti A, Hellstrom-Lindberg E, Giagounidis A, et al. Haplo insufficiency of RPS14 in 5q- syndrome is associated with deregulation of ribosomal- and translation-related genes. Br J Haematol,2008;142(1):57-64
[35]Renneville A, Quesnel B, Charpentier A, et al. High occurrence of JAK2 V617 mutation in refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Leukemia,2006,20:2067-2070
[36]Szpurka H,Tiu R,Murugesan G,et al.Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T),another myeloproliferative condition characterized by JAK2 V617F mutation.Blood,2006,108:2173-2181
[37]livier Kosmider,Veronique Gelsi-Boyer,Meyling Cheok,et al.TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs).Blood.2009;114(15):3285-3291
[38]R Itzykson,Okosmider,T Cluzeau,et aLImpact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias.Leukemia,2011:1-6
[39]陈婉.骨髓增生异常综合征患者JAK2和TET2基因突变的检测及临床意义[D].苏州：苏州大学,2010
[40]钱锡峰,深云峰,张苏江,等.Tet2突变与恶性血液病.中国实验血液学杂志,2010；18(4)：1096-1100
[41]41 Grimwade D, Walker H, Oliver e, et al. The importance of diagnostic cytogenetics on outcome in AML:Analysis of 1612 patients entered into the MRC AML 10 trial. Blood,1998,92(7):2322-2333
[42]Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis acute myeloid leukemia:A southwest Oncology Group/Eastern Cooperative Oncology Group study. Blood,2000,96(12):4075-4083
[43]Mrozek K, Heerema NA, Bloomfield CD. Cytogenetics in acute leukemia. Blood Rev,2004; 18(2):115-136
[44]Choudhary C, Muller-Tidow C, Berdel WE, et al. Signal transduction of oncogenic Flt3. Int J Hematol,2005;82(2):93-99
[45]Yanada M, Matsuo K, Suzuki T, et al. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia:a meta-analysis. Leukemia,205;19(8):1345-1349
[46]Neubauer A, Dodge RK, George SL, et al. Prognostic importance of mutations in the rsa proto-oncogenes in de novo acute myeloid leukemia. Blood,1994; 83(6): 1603-1611
[47]Olivier Kosmider, Eric Delabesse, Veronique Mansat-DeMas, et al. TET2 mutations in secondary acute myeloid leukemias:a French retorspective study. haematologica,2011 Apr 20.[Epub ahead of print]
[48]SMC Langemeijer,JH Jansen,J Hooijer,et al.TET2 mutations in childhood leukemia.leukemia,2011;25:189-192
[49]Ulrike Bacher,Torsten Haferlach,susanne Schnittger,et al.Recent advances in diagnosis,molecular pathology and therapy of chronic myelomonocytic leukaemia.British Journal of Haematology,2011;153(2):149-167
[50]Olivier Kosmider, Veronique Gelsi-boyer, Marion Ciudad, et al. TET2 gene mutation is a frequent and adverse event in chronic myelomonocytic leuke-mia.Haematologica,2009;94(12):1676-1681
[51]李红,高琳,沈柱,等.肥大细胞增生症的研究进展.国际皮肤性病学杂志,2006；32(6)：383-385.
[52]Garcia-Montero AC, Jara-Acevedo M, Teodosio C, et al. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders:a pospective study of the Spanish Network on Mastocytosis(REMA) in a series of 113 patients. Blood,2006; 108(7):2366-2372
[53]Kahler C, Didlaukat S, Feller AC, et al. Sensitive and reliable detection of Kit point mutation Asp 816 to Val in pathological material. Diagn Pathol,2007;2:37
[54]吴贤杰,郑敏.细胞增生症与干细胞因子受体(c-kit)突变的关系.国外医学：生理病理科学与临床分册,2005；1：87-90
[55]Tefferi, RL Levine, K-H Lim, et al. Frequent TET2 mutations in systemic mastocytosis:clinical,KITD816V and FIP1L1-PDGFRA correlates.Leukemia, 2009;23(5):900-904
[2]Martha Wadleigh,Ayalew Tefferi.Classification and diagnosis of myeloprolife-rative neoplasms according to the 2008 World Health Organization criteria.Int J Hematol.2010;91(2):174-179
[3]Runxiang Zhao, Shu Xing, Zhe Li,et al. The Japanese Society of Hematology 2010 Identification of an Acquired JAK2 Mutation in Polycythemia Vera.The Journal Of Biological Chemistry.2005; 280(24):22788-22792
[4]E Joanna Baxter,Linda M Scott,Peter J Campbell,et al. Acquired mutation of the tyrosine kinase JAK2 in human mycloproliferative disorders.The Lancet. 2005;365(9464):1054-1061
[5]Chloe James,Valeris Ugo,Jean-Pierre Le Couedic,et al.A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera.Nature. 2005;434(67):1144-1148
[6]SJ Baker, SG Rane, EP Reddy. Hematopoietic cytokine receptor signaling. Oncogene.2007;26:6724-6737
[7]Reuther Gary W. JAK2 activation in myeloproliferative neoplasms:A potential role for heterodimeric receptors. Landes Bioscience.2008;7(6):714-719
[8]吴迪炯,孙洁,周郁鸿.骨髓增殖性疾病的认知和治疗.国陆军输血及血液学杂志,2010；33(3)：276-279
[9]顾树程,常春康.JAK2V617F在骨髓增殖性肿瘤中的研究进展.现代中西医结合杂志,2010；19(6)：769-771
[10]O kilpivaara, RL Levine. JAK2 and MPL mutations in myeloproliferative neoplasms:discovery and science. Leukemia,2008;22:1813-1817
[11]A Tefferi. The history of myeloproliferative disorders:before and after Dameshek. Leukemia,2008;22:3-13
[12]Ayalew Tefferi, D Gary Gilliand. Oncogenes in myeloproliferative Disorders. Landes Bioscience,2007;5:550-566
[13]David P, Steensma,Gordon W,et al.The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and myelodysplastic syndromes.Blood.2005; 106(4):1207-1209
[14]Frohling S,Lipka DB,Kayser S,et al.Rare occurrence of the JAK2V617F mutation in AML subtypes M5,M6,and M7.Blood,2006; 107:1242-1243
[15]Peter J,Campbell E,Joanna Baxter,et al.Mutation of JAK2 in the myeloproliferative disorders:timing,clonality studies,cytogenetic associations, and role in leukemic transformation.Blood.2006;108(10):3548-3555
[16]Alexandre Theocharides,Marjorie Boissinot,Francois Girodon,et al.Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation. Blood.2007; 110(1):375-379
[17]DelhommeauF,DupontS,JamesC,etal.TET2 isa noveltumor suppressor gene inac-tivated in myeloproliferative neoplasms:identification of a Pre-JAK2 V617F event. ASH Annual Meeting Abstracts 2008; 112:lba-3
[18]Omar Abdel-Wahab,Ann Mullally,Cyrus Hedvat,et al.Genetic characterization of TET1,TET2,and TET3 alterations in myeloid malignancies.Blood.2009; 114(1):144-147
[19]Olivier Kosmider,Veronique Gelsi-Boyer,Meyling Cheok,et al.TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs).Blood.2009;114(15):3285-3291
[20]Sabina I,Swierczek,Donghoon Yoon,et al.Extent of hematopoietic involvement by TET2 mutations in JAK2V617F polycythemia vera.Haematologica.2010; 96(5):775-778
[21]Olivier Kosmider, Veronique Gelsi-Boyer, Marion Ciudad, et al. TET2 gene mutation is a frequent and adverse event in chronic myelomonocytic leukemia. haematologica,2009;94(12):1676-1681
[22]Olivier Kosmider, Eric Delabesse, Veronique Mansat-deMas, et al. TET2 mutations in secondary acute myeloid leukemias:a French retrospective study. Haematologica,2011 Apr 20. [Epub ahead of print]
[23]A Tefferi,RL Levine,K-H Lim,et al. Frequent TET2 mutations in systemic mastocytosis:clinical,KITD816V and FIP1L1-PDGFRA correlaties.Leukemia. 2009;23(5):900-904
[24]Franz X.Schaub,Renate Looser,et al.Clonal analysis of TET2 and JAK2 mutations suggests that TET2 can be a late event in the progression of myeloproliferative neoplasms.Blood.2010; 115(10):2003-2007
[25]Saskia M C Langemeijer,Roland P Kuiper,Marieke Berends,et al.Acquired mutations in TET2 are common in myelodysplastic syndromes.Nature Gene-tics.2009;41(7):838-843
[26]A Tefferi,Apardanai,K-H Lim,et al.TET2 mutations and their clinical correla-tes in polycythemia vera,essential thrombocythemia and myelofibrosis. Leuke-mia.2009;23(5):905-911
[27]A Tefferi, K-H Lim, O Abdel-Wahab, et al. Detection of mutant TET2 in myeloid malignancies other than myeloproliferative meoplasms:CMML, MDS, MDS/MPN and AML.Leukemia.2009;23(7):1343-1345
[28]Delhommeau F, Dupont S, Della Valle V,et al.Mutation in TET2 in Myeloid Cancers. The New England Journal of Medicine.2009;360(22):2289-2301
[29]Campbell PJ,Griesshammer M,Dohner K,et al. V617F mutation in JAK2 is associated with poorer survival in idiopathic myelofibrosis. Blood,2005; 107(5): 2098-2100
[30]Mc Clure R, Mai M, Lasho T, et al. Validation of two clinically useful assays for evalution of JAK2-V617F mutation in chronic myeloproliferative disorders. Leukemia,2006;20(1):168-171
[31]袁利亚,李红,陈国安,等JAK2 V617F基因突变在骨髓增生性疾病中的发生率及其临床意义.浙江大学学报(医学版),2010；39(2)：202-206
[32]张苏江,李伟达,宋君红,等.等位基因特异性聚合酶链反应结合测序对骨髓增殖性疾病JAK2 V617F点突变的研究。中华医学杂志,2007；87(30)：2109-2112
[33]Tefferi A. JAK2 mutations and clinical practice in myeloproliferative neoplasms. Cancer J,2007; 13:366-371
[34]Panani AD. Janus kinase 2 mutations in Philadelphia negative chronic myeloproliferative disorders:Clinical implications. Cancer Lett,2009; 284(1):7-14
[35]张心菊,顾小叶,刘双春,等.采用荧光定量PCR检测JAK2基因V617F突变.中华检验医学杂志,2009；32(5)：583-586
[36]Morgani KJ,Gilliland DG.A role for JAK2 mutations in myeloproliferative diseases.Ann Rev Med,2008;59:213-222
[37]刘红星,童春容,蔡鹏,等.多重位点特异性PCR检测骨髓增殖性疾病五种JAK2基因突变。中华检验医学杂志,2009；32(1)：30-34
[38]晁红颖,沈益民,张日,等.135例骨髓增殖性肿瘤患者JAK2基因突变的定量研究.中华血液学杂志,2009；30(5)：321-325
[39]Ana Maria Vladareanu,Carsten Mullen-Tidow,Horia Bumbea, et al. Molecular markers guide diagnosis and treatment in Philadelphia chromosome-negative myeloproliferative disorders. Oncology Reports,2010; 23(3):595-604
[40]Jeffery M,Klco,PhD,et al.Molecular Pathology of Myeloproliferative neopl-asm.AM J Clin Pathol,2010;133(4):602-615
[41]A Tefferi, JW Vardiman. Classification and diagnosis of myeloproliferative neoplasms:the 2008 World Health Organization criteria and point-of-care diagnostic algorithms.leukemia,2008;22(1):14-22
[42]林凤茹,郭晓楠.WHO关于慢性骨髓增殖性疾病的分类和诊断标准.临床荟萃,2004；9(9)：539-540
[43]Jones AV,Silver RT,Waghorn K,Curtis C,Kreil S,Zoi K et al.Minimal molecular response in polycythemia vera patients treated with imatinib or interferon alpha.Blood 2006;107(8):3339-3341
[44]Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood,2008; 112(8):2065-3072
[45]Passamonti F,Rumi E,Pietra D,et al.Relation betweenJAK2(V617F) mutation status,granulocyte activation,and constitutive mobilization of CD34+ cells into peripheral blood in myeloproliferative disorders. Blood,2005; 107(9):3676-3682
[46]Barosi G,Bergamaschi G,Marchetti M,et al.JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis.Blood,2007;110(12):4030-4036
[47]A M Vannucchi,E Antonioli,P Guglielmelli,et al.Clinical correlates of JAK2-V617F presence or allele burden in myeloproliferative neoplasms:a critical reappraisal. Leukemia,2008; 22(7),:1299-1307
[48]Torsten Haferlach, Ulrike Bacher, Wolfgang Kern. The diagnosis of BCR/ABL-negative chronic myeloproliferative diseases (CMPD):a comprehe-nsive approach based on morphology, cytogenetics, and molecular markers. Ann Hematol,2008;87(1):1-10
[49]Ross L.Mechanisms of mutations in myeloproliferative neoplasms.Clinical Haematology,2009;22(4):489-494
[50]50Ross L,Levine,Claude Belisle,et al.X-inactivation-based clonality analysis and quantitative JAK2V617F assessment reveal a strong association between clonality and JAK2V617F in PV but not ET/MMM,and identifies a subset of JAK2V617F-negative ET and MMM patients with clonal hematopoiesis. Blood,2006;107(10):4139-4141
[51]Gurunathan Murugesan,Samer Aboudola,Hadrian Szpurka.Identification of the JAK2V617F mutation in chronic myeloproliferative disorders using FRET probes and melting curve analysis.Am J Clin Pathol,2006(4); 125:625-633
[52]Villeval JL,James C,Pisani DF,et al.New insights into the pathogenesis of JAK2 V617F-positive myeloproliferative disorders and consequences for the management of patients. Semin Thromb Hemost,2006;32(4Pt):341-351
[53]Lacout C, Pisani DF, Tulliez M, etal. JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary mylopibrosis. Blood,2006; 108:1652-1660
[54]Tefferi A,Lasho TL,Schwager SM,et al.The clinical phenotype of wild-type,heterozygous,and homozygous JAK2V617F in polycythemia vera. Cancer, 2006;106(3):631-635
[55]Campbell PJ,Scott LM,Buck G,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
[56]刘红星,童春荣,蔡鹏,等。真性红细胞增多症和原发性血小板增多症JAK2V617F基因纯合突变克隆分析。首都医科大学学报2008；29：113-117
[57]Tefferi A, Lasho TL, Schwaqer SM,et al. The clinical phenotype of wild type, heterozygous,and homozygous JAK2V617F in polycythemia vera. Cancer,2006; 106(3):631
[58]楼瑾,李玉珠,杜新,等。JAK2 V617F点突变在真性红细胞增多症中的诊断价值.岭南急诊医学杂志,2010；15(3)：176-177
[59]Fabian Mohr,K onstanze Dohner,Christian Buske,et al.TET Genes:new players in DNA demethylation ad important determinants for sternness. Experimental Hematology,2011;39(3):272-281
[60]SMC Langemeijer,JH Jansen,J Hooijer,et al.TET2 mutations in childhood leukemia.Leukemia,2011;25(1):189-192
[61]Bellanne-Chantelot C, Chaumarel I, Labopin M, et al. Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders.blood,2006; 108:346-352
[62]Omar Abdel-wahab, Taghi Manshouri, Jaypatel, et al. Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias.Cancer Res,2010;70(2):447-452
[1]苗振静,马旭辉。颅内恶性肿瘤发病机制研究进展.实用医药杂志,2010；27(2)：173-176
[2]唐颖.甲状腺癌相关基因研究进展.诊断病理学杂志,2010；17(5)：386-389.
[3]程广保,保璟霞.乳腺癌发病的基因调控机制.现代肿瘤医学,2010；18(9)：1848-1852
[4]周健.肝门胆管癌的基因组学.检验医学与临床,2010；7(18)：2021-2023.
[5]吕强,邢沈阳,赵志辉,等.结肠癌的研究现状及展望.中国实验诊断学,2009；13(8)：1134-1136
[6]翟洪顺,邹德学,聂李平,等.微分化急性髓系白血病病人MICM特征分析.现代医学仪器与应用,2008；2：4-10
[7]李正发,沈晓梅,王云娟,等.白血病MICM分开的临床和实验研究.昆明医学院学报,2001；1：9-13
[8]Ayton PM,Cleary ML.Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins.Oncogene 2001;20(40):5695-5707
[9]Lorsbach RB,M oore J,Mathew S,et al.tetl,a member of a novel protein family,is fused to MLL in acute myeloid leukemia containing the t(10;11) (q22;q23). Leukemia,2003; 17(3):637-641
[10]F Viguie,A Aboura,D Bouscary,et al.Common 4q24 deletion in four cases of hematopoietic malignancy:early stem cell involvement?Leukemia,2005; 19(8): 1411-1415
[11]Delhommeau F,Dupont S,James C,et al.Tet2 is a novel turn or suppressor gene inactivated in myeloproliferative neoplasms identification of a pre- JAK2 V617F event.ASH Annu Meet Abstr,2008;112:Iba-3
[12]Saskia M C Langemeijer,Roland P Kuiper,Marieke Berends,et al.Acquired mutations in TET2 are common in myelodysplastic syndromes. Nature Genetics, 2009;41(7):838-842
[13]Fabian Mohr,Konstanze Dohner,Christian Buske,et al.TET Genes:new players in DNA demethylation and important determinants for stemness.Experimental Hematology,2011;39(3):272-281
[14]A Tefferi,K-H Lim,O Abdel-Wahab,et al.Detection of mutant TET2 in myeloid malignancies other than myeloproliferative meoplasm:CMML,MDS, MDS/ MPN and AML.Leukemia.2009;23(7):1343-1345
[15]Delhommeau F, Dupont S, Della Valle V,et al.Mutation in TET2 in Myeloid Cancers. The New England Journal of Medicine.2009;360(22):2289-2301
[16]Baker, SG Rane, EP Reddy.hematopoietic cytokine receptor signaling. Oncogene, 2007;26,6724-6737
[17]Jeffery M Klco,Ravi Vij,Friederike H Kreisel,et al.Molecular Pathology of Myeloproliferative Neoplasms.Am J Clin Pathol 2010; 133:602-615
[18]Ross L Levine.Mechanisms of mutations in myeloproliferative neoplasms. Clinical Haematology,2009;22(4):489-494
[19]Scott LM,Tong W,Levine RL,et al.JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis.N Engl J Med,2007;356:459-468
[20]Pardanani AD,Levine RL,Lasho T,et al.MPL515 mutations in myeloproliferative and other myeloid disorders:a study of 1182 patients.Blood,2006; 108:3472-3476
[21]Pikman Y,Lee BH,Mercher T,et al.MPL W515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia.PLoS Med,2006;3:e270
[22]Tefferi A, Thiele J, Orazi A, et al. Proposals and rationale for revision of the world Health Organization diagnostic criteria for polycythemia vera,essential thrombocythemia,and primary myelofibrosis:recommendations from an ad hoc international expert panel. Blood,2007; 110:1092-1097
[23]Tefferi,A Pardanani,K-H Lim,et al.TET2 mutations and their clinical correlates in polycythemia vera,essential thrombocythemia and myelofibrosis. leukemia, 2009;23(5):905-911
[24]Omar Abdel-Wahab,Ann Mullally,Cyrus Hedvat,et al.Genetic characterization of TET1,TET2,and TET3 alterations in myeloid malignancies. Blood.2009;114: 144-147
[25]Franz X.Schaub,Renate Looser,et al.Clonal analysis of TET2 and JAK2 mutations suggests that TET2 can be a late event in the progression of myeloproliferative neoplasms.Blood.2010; 115:2003-2007
[26]Omar Abdel-wahab, Taghi Manshouri, Jaypatel, et al. Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias.Cancer Res,2010;70:447-452
[27]Sabina I,Swierczek,Donghoon Yoon,et al.Extent of hematopoietic involvement by TET2 mutations in JAK2V617F polycythemia vera.Haematologica.2010; 96(5):775-778
[28]Dicker F, Haferlach C, Kern W, et al. RUNX1 mutations play a major role in the progression of MDS to sAML following MDS:a genetic and cytogenetic snalysis of sequential samples. Blood,2008;112:3634
[29]Pedersen-Bjergaard J, Pedersen M, Roulston D, et al. Different genetic pathways in leukemogenesis for patients presenting with therapy-related myelodysplasia and therapy-related acute myeloid leukemia. Blood,1995; 86(9); 3542-3552
[30]List AF, Vardiman J, Issa JP, et al. Myelodysplastic syndromes. Hematology Am Sco Hemtol Educ Program,2004; 297-317
[31]Hasse D, Germing U, Schanz j, et al. Insights into the prognostic impact of the karyotype in MDS and correlation with subtypes evidence from a core dataset of 124 patients. Blood,2007;110(13):4385-4395
[32]Nolte F, Hofmann WK. Myelodysplastic syndromes molecular pathogenesis and genomic changes. Ann Hematol,2008;87(10):777-795
[33]Ebert BL, Pretzl J, Bosco J, et al. Identification of RPS14 as a 5q- syndrome gene by RNA interference screen. Nature,2008;451(7176):335-339
[34]Pellagatti A, Hellstrom-Lindberg E, Giagounidis A, et al. Haplo insufficiency of RPS14 in 5q- syndrome is associated with deregulation of ribosomal- and translation-related genes. Br J Haematol,2008;142(1):57-64
[35]Renneville A, Quesnel B, Charpentier A, et al. High occurrence of JAK2 V617 mutation in refractory anemia with ringed sideroblasts associated with marked thrombocytosis. Leukemia,2006,20:2067-2070
[36]Szpurka H,Tiu R,Murugesan G,et al.Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T),another myeloproliferative condition characterized by JAK2 V617F mutation.Blood,2006,108:2173-2181
[37]livier Kosmider,Veronique Gelsi-Boyer,Meyling Cheok,et al.TET2 mutation is an independent favorable prognostic factor in myelodysplastic syndromes (MDSs).Blood.2009;114(15):3285-3291
[38]R Itzykson,Okosmider,T Cluzeau,et aLImpact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias.Leukemia,2011:1-6
[39]陈婉.骨髓增生异常综合征患者JAK2和TET2基因突变的检测及临床意义[D].苏州：苏州大学,2010
[40]钱锡峰,深云峰,张苏江,等.Tet2突变与恶性血液病.中国实验血液学杂志,2010；18(4)：1096-1100
[41]41 Grimwade D, Walker H, Oliver e, et al. The importance of diagnostic cytogenetics on outcome in AML:Analysis of 1612 patients entered into the MRC AML 10 trial. Blood,1998,92(7):2322-2333
[42]Slovak ML, Kopecky KJ, Cassileth PA, et al. Karyotypic analysis acute myeloid leukemia:A southwest Oncology Group/Eastern Cooperative Oncology Group study. Blood,2000,96(12):4075-4083
[43]Mrozek K, Heerema NA, Bloomfield CD. Cytogenetics in acute leukemia. Blood Rev,2004; 18(2):115-136
[44]Choudhary C, Muller-Tidow C, Berdel WE, et al. Signal transduction of oncogenic Flt3. Int J Hematol,2005;82(2):93-99
[45]Yanada M, Matsuo K, Suzuki T, et al. Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia:a meta-analysis. Leukemia,205;19(8):1345-1349
[46]Neubauer A, Dodge RK, George SL, et al. Prognostic importance of mutations in the rsa proto-oncogenes in de novo acute myeloid leukemia. Blood,1994; 83(6): 1603-1611
[47]Olivier Kosmider, Eric Delabesse, Veronique Mansat-DeMas, et al. TET2 mutations in secondary acute myeloid leukemias:a French retorspective study. haematologica,2011 Apr 20.[Epub ahead of print]
[48]SMC Langemeijer,JH Jansen,J Hooijer,et al.TET2 mutations in childhood leukemia.leukemia,2011;25:189-192
[49]Ulrike Bacher,Torsten Haferlach,susanne Schnittger,et al.Recent advances in diagnosis,molecular pathology and therapy of chronic myelomonocytic leukaemia.British Journal of Haematology,2011;153(2):149-167
[50]Olivier Kosmider, Veronique Gelsi-boyer, Marion Ciudad, et al. TET2 gene mutation is a frequent and adverse event in chronic myelomonocytic leuke-mia.Haematologica,2009;94(12):1676-1681
[51]李红,高琳,沈柱,等.肥大细胞增生症的研究进展.国际皮肤性病学杂志,2006；32(6)：383-385.
[52]Garcia-Montero AC, Jara-Acevedo M, Teodosio C, et al. KIT mutation in mast cells and other bone marrow hematopoietic cell lineages in systemic mast cell disorders:a pospective study of the Spanish Network on Mastocytosis(REMA) in a series of 113 patients. Blood,2006; 108(7):2366-2372
[53]Kahler C, Didlaukat S, Feller AC, et al. Sensitive and reliable detection of Kit point mutation Asp 816 to Val in pathological material. Diagn Pathol,2007;2:37
[54]吴贤杰,郑敏.细胞增生症与干细胞因子受体(c-kit)突变的关系.国外医学：生理病理科学与临床分册,2005；1：87-90
[55]Tefferi, RL Levine, K-H Lim, et al. Frequent TET2 mutations in systemic mastocytosis:clinical,KITD816V and FIP1L1-PDGFRA correlates.Leukemia, 2009;23(5):900-904