骨髓增殖性肿瘤患者JAK2V617F突变与临床特征的关联性分析及其临床意义

doi:10.13481/j.1671-587x.20190523

摘要/Abstract

摘要： 目的：研究JAK2V617F突变在骨髓增殖性肿瘤（MPN）患者中的分布情况，探讨JAK2V617F突变与MPN临床特征的关联性，阐明其在MPN患者诊疗过程中的临床意义。方法：选择170例MPN患者作为研究对象，将其分为真性红细胞增多症（PV）组（n=68）、原发性血小板增多症（ET）组（n=88）和原发性骨髓纤维化（PMF）组（n=14），采用等位基因特异性PCR（AS-PCR）法检测170例MPN患者JAK2V617F突变情况，分析各组内JAK2V617F突变型与野生型患者性别分布、年龄、白细胞计数、血红蛋白、血小板计数、凝血酶原时间（PT）、活化部分凝血活酶时间（APTT）、D-二聚体水平、是否并发脾肿大和血栓栓塞方面的差别。结果：在170例MPN患者中JAK2V617F的总突变率为68.2%（116/170），PV、ET和PMF组的突变率分别为72.1%（49/68）、68.1%（60/88）和50.0%（7/14），PV组患者中的JAK2V617F突变率高于其他2组，但差异无统计学意义（P=0.281）。与野生型组比较，JAK2V617F突变型PV患者发病年龄、白细胞和血小板计数明显升高（P<0.01），PT和APTT明显延长（P<0.01），脾肿大发生率升高（P<0.05）；JAK2V617F突变型ET患者白细胞计数升高（P<0.01），血红蛋白水平降低（P<0.01），APTT明显延长（P<0.01），血栓栓塞事件发生率升高（P<0.05）；JAK2V617F突变型PMF患者发病年龄增加（P<0.05），白细胞和血小板计数升高（P<0.05或P<0.01）。与JAK2V617F突变型ET和PMF患者比较，JAK2V617F突变型PV患者APTT明显延长（P<0.05）；与JAK2V617F突变型PV和ET患者比较，JAK2V617F突变型PMF患者发病年龄增加及白细胞计数升高（P<0.05）。结论： JAK2V617F突变型MPN患者与野生型患者临床特征明显不同；JAK2V617F突变型MPN患者中PV、ET和PMF临床特征也不尽相同，JAK2V617F突变型PV患者更易发生APTT延长，JAK2V617F突变型PMF患者发病年龄更大且白细胞计数更高。

关键词: 骨髓增殖性肿瘤, JAK2V617F基因突变, 白细胞计数, 活化部分凝血活酶时间, 血栓形成

Abstract: Objective:To investigate the distribution of JAK2V617F mutation in the patients with myeloproliferative neoplasms (MPN), to explore the association between JAK2V617F mutation and the clinical features of MPN, and to clarify its clinical significance in the diagnosis and treatment of the MPN patients. Methods:A total of 170 patients with MPN were selected as the subjects and divided into true polycythemia (PV) group (n=68), primary thrombocytopenia (ET) group (n=88) and primary myelofibrosis (PMF) group (n=14).The JAK2V617F mutations in 170 patients with MPN were detected by allele-specific PCR (AS-PCR). The differences in gender, age, white blood cell count, hemoglobin,platelet count, prothrombin time(PT),activated partial thromboplastin time(APTT), D-dimer, whether complicated with splenomegaly and thromboembolism of the JAK2V617F mutant-type and wild-type patients in each group were analyzed. Results:The total mutation rate of JAK2V617F mutation in 170 patients with MPN was 68.2% (116/170),and the mutation rates in PV, ET, and PMF groups were 72.1% (49/68), 68.1% (60/88), and 50.0% (7/14), respectively.The JAK2V617F mutation rate in PV group was higher than those in the other two groups, but there were no statistical differences(P=0.281). Compared with wild type group, the age of onset, the white blood cell and platelet counts of the PV patients with JAK2V617F mutation were significantly increased(P<0.01), PT and APTT were significantly prolonged(P<0.01), and the incidence of splenomegaly was increased (P<0.05); the white blood cell count of the the ET patients with JAK2V617F mutation was increased(P<0.01),the hemoglobin level was decreased(P<0.01), APTT was significantly prolonged(P<0.01), and the incidence of thromboembolic events was increased (P<0.05); the age of onset, the white blood cell and platelet counts of the PMF patients with JAK2V617F mutation were signficantly increased (P<0.05 or P<0.01).Compared with the ET and PMF patients with JAK2V617F mutation, APTT in the PV patients with JAK2V617F mutation was significantly prolonged(P<0.05). Compared with the JAK2V617F mution PV and ET patients, the age of onset and white blood cell count of the PMF patients with JAK2V617F mutation were increased(P<0.05). Conclusion:The clinical characteristics of the MPN patients with JAK2V617F mutation are significantly different from those in the wild-type patients. The clinical features of PV, ET and PMF in the patients with JAK2V617F mutation are also different. The PV patients with JAK2V617F mutation are more prone to APTT prolongation. The PMF patients with JAK2V617F mutation have the higher onset age and the white blood cell count.

Key words: myeloproliferative neoplasms, JAK2V617F mutation, white blood cell count, activated partial thromboplastin time, thrombosis

中图分类号:

R733.3

胡晓, 於秋燕, 徐文, 王春红, 金立方, 金鑫, 李小丰, 王秀丽, 于晓艳, 李景贺. 骨髓增殖性肿瘤患者JAK2V617F突变与临床特征的关联性分析及其临床意义[J]. 吉林大学学报(医学版), 2019, 45(05): 1106-1112.

HU Xiao, YU Qiuyan, XU Wen, WANG Chunhong, JIN Lifang, JIN Xin, LI Xiaofeng, WANG Xiuli, YU Xiaoyan, LI Jinghe. Correlation analysis on JAK2V617F mutation and clinical features in patients with myeloproliferative neoplasms and its clinical significance[J]. Journal of Jilin University(Medicine Edition), 2019, 45(05): 1106-1112.

参考文献

[1] LEVINE R L.Another piece of the myeloproliferative neoplasms puzzle[J].N Engl J Med,2013,369(25):2451-2452.
[2] BAXTER E J, SCOTT L M, CAMPBELL P J, et al.Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders[J].Lancet,2005,365(9464):1054-1061.
[3] LEVINE R L, WADLEIGH M,COOLS J,et al.Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis[J].Cancer Cell,2005,7(4):387-397.
[4] NUNES D P,LIMA L T,CHAUFFAILLE M D E L,et al.CALR mutations screening in wild type JAK2(V617F) and MPL(W515K/L) Brazilian myeloproliferative neoplasm patients[J].Blood Cells Mol Dis,2015,55(3):236-240.
[5] ARBER D A, ORAZI A,HASSERJIAN R,et al.The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia[J].Blood,2016,127(20):2391-2405.
[6] SABATTINI E,BACCI F,SAGRAMOSO C,et al.WHO classification of tumours of haematopoietic and lymphoid tissues in 2008:an overview[J]. Pathologica, 2010,102(3):83-87.
[7] WOLANSKYJ A P,LASHO T L,SCHWAGER S M,et al.JAK2 mutation in essential thrombocythaemia:Clinical associations and long-term prognostic relevance[J].Br J Haematol,2005,131(2):208-213.
[8] TEFFERI A.JAK2 mutations and clinical practice in myeloproliferative neoplasms[J].Cancer J,2007,13(6):366-371.
[9] CAMPBELL P J, GREEN A R.The myeloproliferative disorders[J].N Engl J Med,2006,355(23):2452-2466.
[10] SAHARINEN P,TAKALUOMA K, SILVENNOINEN O.Regulation of the JAK2 tyrosine kinase by its pseudokinase domain[J].Mol Cell Biol,2000, 20(10):3387-3395.
[11] SAHARINEN P,SILVENNOINEN O.The pseudokinase domain is required for suppression of basal activity of JAK2 and JAK3 tyrosine kinases and for cytokine-inducible activation of signal transduction[J].J Biol Chem,2002,277(49):47954-47963.
[12] RAMPAL R,AL-SHAHROUR F,ABDEL-WAHAB O,et al.Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis[J].Blood,2014,123(22):e123-e133.
[13] PASSAMONTI F,RUMI E,PIETRA D,et al.A prospective study of 338 patients with polycythemia vera:the impact of JAK2(V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications[J].Leukemia,2010,24(9):1574-1579.
[14] 贾晓阳,王光平.JAK2V617F基因突变在骨髓增殖性肿瘤诊断中的应用[J].中国现代医学杂志,2015,25(26):46-49.
[15] 尹春荣,翁巍,侯海珠,等. JAK2V617F基因突变与BCR/ABL阴性骨髓增殖性肿瘤的临床相关性分析[J].中华全科医学,2016,14(8):1299-1301,1337.
[16] LIM Y, LEE J O, KIM S H, et al. Prediction of thrombotic and hemorrhagic events during polycythemia vera or essential thrombocythemia based on leukocyte burden[J].Thromb Res,2015,135(5):846-851.
[17] YESILOVA A M, YAVUZER S, YAVUZER H,et al. Analysis of thrombosis and bleeding complications in patients with polycythemia vera:a Turkish retrospective study[J]. Int J Hematol,2017,105(1):70-78.
[18] MARCHIOLI R,FINAZZI G,LANDOLFI R,et al.Vascular and neoplastic risk in a large cohort of patients with polycythemia vera[J].J Clin Oncol,2005,23(10):2224-2232.
[19] VANNUCCHI A M,LASHO T L,GUGLIELMELLI P,et al.Mutations and prognosis in primary myelofibrosis[J].Leukemia,2013,27(9):1861-1869.
[20] MISAWA K, YASUDA H, ARAKI M,et al.Mutational subtypes of JAK2 and CALR correlate with different clinical features in Japanese patients with myeloproliferative neoplasms[J]. Int J Hematol,2018,107(6):673-680.
[21] TEFFERI A,RUMI E,FINAZZI G,et al.Survival and prognosis among 1545 patients with contemporary polycythemia vera:an international study[J].Leukemia,2013,27(9):1874-1881.
[22] PASSAMONTI F,THIELE J,GIRODON F,et al.A prognostic model to predict survival in 867 World Health Organization-defined essential thrombocythemia at diagnosis:a study by the International Working Group on Myelofibrosis Research and Treatment[J].Blood,2012,120(6):1197-1201.
[23] CERVANTES F,DUPRIEZ B,PEREIRA A, et al.New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment[J].Blood,2009,113(13):2895-2901.
[24] RUMI E,PIETRA D,PASCUTTO C,et al.Clinical effect of driver mutations of JAK2,CALR,or MPL in primary myelofibrosis[J].Blood,2014,124(7):1062-1069.
[25] TEFFERI A,GUGLIELMELLI P, LARSON D R,et al.Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis[J].Blood,2014,124(16):2507-2513.