真性红细胞增多症患者JAK2基因突变的临床意义
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摘要
真性红细胞增多症(polycythemia vera,PV)为一种以红细胞增多为特征的骨髓增殖性肿瘤(myeloproliferative neoplasm,MPN)。PV的发病机制尚未阐明,可能和JAK2基因的功能获得性体细胞突变相关,JAK2基因突变为PV提供了分子学诊断标准。JAK2基因突变和等位基因突变负荷可推测PV患者的临床特征和发展趋势。JAK2基因突变的发现促进了分子靶向治疗的发展,JAK2抑制剂ruxolitinib已应用于临床,治疗效果和安全性均良好。JAK2等位基因突变负荷与白细胞增多、转化为骨髓纤维化(myelofibrosis,MF)密切相关,高JAK2等位基因突变负荷可能为PV患者预后不良的危险因素。本文对PV患者JAK2基因突变的临床意义进行综述。
Polycythemia vera(PV) is a myeloproliferative neoplasm(MPN) characterized by overproduction of red blood cells. The pathogenesis of PV is not completely understood. However, studies report that it may be associated with the gain-of-function somatic mutation of JAK2 and that the JAK2 mutation provides a molecular diagnostic standard for PV. JAK2 mutation and allele mutation burden are useful for predicting clinical features and courses. The discovery of JAK2 mutation has promoted the development of molecular-targeted therapy, such as the JAK2 inhibitor, ruxolitinib, a drug with superior therapeutic effect and safety that is used in clinical practice. The JAK2 allele mutation burden is closely associated with leukocytosis and progression to myelofibrosis(MF). A high JAK2 allele mutation burden may be a risk factor for poor prognosis. This article briefly reviews the clinical significance of the JAK2 mutation in patients with PV.
Polycythemia vera(PV) is a myeloproliferative neoplasm(MPN) characterized by overproduction of red blood cells. The pathogenesis of PV is not completely understood. However, studies report that it may be associated with the gain-of-function somatic mutation of JAK2 and that the JAK2 mutation provides a molecular diagnostic standard for PV. JAK2 mutation and allele mutation burden are useful for predicting clinical features and courses. The discovery of JAK2 mutation has promoted the development of molecular-targeted therapy, such as the JAK2 inhibitor, ruxolitinib, a drug with superior therapeutic effect and safety that is used in clinical practice. The JAK2 allele mutation burden is closely associated with leukocytosis and progression to myelofibrosis(MF). A high JAK2 allele mutation burden may be a risk factor for poor prognosis. This article briefly reviews the clinical significance of the JAK2 mutation in patients with PV.
引文
[1]Spivak JL.Myeloproliferative neoplasms[J].Clin Lymph Myelo Leuke,2015,15(1):S19-S26.
[2]Vainchenker W,Kralovics R.Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms[J].Blood,2017,129(6):667-679.
[3]Grinfeld J,Godfrey AL.After 10 years of JAK2V617F:Disease biology and current management strategies in polycythaemia vera[J].Blood Rev,2017,31(3):101-118.
[4]Rumi E,Cazzola M.Diagnosis,risk stratification,and response evaluation in classical myeloproliferative neoplasms[J].Blood,2017,129(6):680-692.
[5]Hasselbalch HC,Bj?rn ME.Ruxolitinib versus standard therapy for the treatment of polycythemia vera[J].New Engl J Med,2015,372(17):1670.
[6]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.
[7]Vannucchi AM,Antonioli E,Guglielmelli P,et al.Prospective identification of high-risk polycythemia vera patients based on JAK2(V617F)allele burden[J].Leukemia,2007,21(9):1952-1959.
[8]Passamonti F,Elena C,Schnittger S,et al.Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon12 mutations[J].Blood,2011,117(10):2813-2816.
[9]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.
[10]Nangalia J,Green AR.Myeloproliferative neoplasms:from origins to outcomes[J].Blood,2017,2017(1):2475-2483.
[11]Tefferi A,Rumi E,Finazzi G,et al.Survival and prognosis among 1 545patients with contemporary polycythemia vera:an international study[J].Leukemia,2013,27(9):1874-1881.
[12]Rampal R,Ahn J,Abdel-wahab O,et al.Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms[J].Proc Natl Acad Sci U S A,2014,111(50):E5401-E5410.
[13]Grinfeld J,Nangalia J.Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms[J].Haematologica,2017,102(1):7-17.
[14]Vannucchi AM,Verstovsek S,Guglielmelli P,et al.Ruxolitinib reduces JAK2 p.V617F allele burden in patients with polycythemia vera enrolled in the response study[J].Ann Hematol,2017,96(7):1113-1120.
[15]Bertozzi I,Bogoni G,Biagetti G,et al.Thromboses and hemorrhages are common in MPN patients with high JAK2V617F allele burden[J].Ann Hematol,2017,96(8):1-6.
[16]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.
[17]Bartels S,Faisal M,Büsche G,et al.Fibrotic progression in polycythemia vera is associated with early concomitant driver-mutations besides JAK2[J].Leukemia,2017,32(2):556-558.
[18]Tsuruta-Kishino T,Koya J,Kataoka K,et al.Loss of p53 induces leukemic transformation in a murine model of Jak2 V617F-driven polycythemia vera[J].Oncogene,2017,36(23):3300-3311.
[19]史仲珣,肖志坚.真性红细胞增多症诊断与治疗中国专家共识(2016年版)解读[J].中华血液学杂志,2016,37(10):852-857.
[20]Alvarez-Larrán A,Pereira A,Cervantes F,et al.Assessment and prognostic value of the European leukemia Net criteria for clinicohematologic response,resistance,and intolerance to hydroxyurea in polycythemia vera[J].Blood,2012,119(6):1363-1369.
[21]Passamonti F,Maffioli M.The role of JAK2 inhibitors in MPNs 7 years after approval[J].Blood,2018,131(5):2426-2435.
[22]Griesshammer M,Saydam G,Palandri F,et al.Ruxolitinib for the treatment of inadequately controlled polycythemia vera without splenomegaly:80-week follow-up from the response-2 trial[J].Ann Hematol,2018,97(5):1591-1600.
[23]Lussana F,Rambaldi A.Inflammation and myeloproliferative neoplasms[J].J Autoimmun,2017,(85):58-63.
[24]Passamonti F,Giorgino T,Mora B,et al.A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis[J].Leukemia,2017,(31):2726-2731.
[25]Lussana F,Rambaldi A,Finazzi MC,et al.Allogeneic hematopoietic stem cell transplantation in patients with polycythemia vera or essential thrombocythemia transformed to myelofibrosis or acute myeloid leukemia:a report from the MPN Subcommittee of the chronic malignancies working party of the european group for blood and marrow transplantation[J].Haematol,2014,99(4):916-921.
[26]Barbui T,Tefferi A,Vannucchi AM,et al.Philadelphia chromosomenegative classical myeloproliferative neoplasms:revised management recommendations from European Leukemia Net[J].Leukemia,2018,32(5):1057-1069.
[27]Bonicelli G,Abdulkarim K,Mounier M,et al.Leucocytosis and thrombosis at diagnosis are associated with poor survival in polycythaemia vera:a population-based study of 327 patients[J].Br JHaematol,2013,160(2):251-254.
[28]Tefferi A,Lasho TL,Guglielmelli P,et al.Targeted deep sequencing in polycythemia vera and essential thrombocythemia[J].Blood Adv,2016,1(2):21-30.
[29]Geyer H,Scherber R,Kosiorek H,et al.Symptomatic profiles of patients with polycythemia vera:Implications of inadequately controlled disease[J].J Clin Oncol,2016,34(2):151-159.
[30]Barbui T,Masciulli A,Marfisi MR,et al.White blood cell counts and thrombosis in polycythemia vera:a subanalysis of the CYTO-PV study[J].Blood,2015,126(4):560-561.
[2]Vainchenker W,Kralovics R.Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms[J].Blood,2017,129(6):667-679.
[3]Grinfeld J,Godfrey AL.After 10 years of JAK2V617F:Disease biology and current management strategies in polycythaemia vera[J].Blood Rev,2017,31(3):101-118.
[4]Rumi E,Cazzola M.Diagnosis,risk stratification,and response evaluation in classical myeloproliferative neoplasms[J].Blood,2017,129(6):680-692.
[5]Hasselbalch HC,Bj?rn ME.Ruxolitinib versus standard therapy for the treatment of polycythemia vera[J].New Engl J Med,2015,372(17):1670.
[6]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.
[7]Vannucchi AM,Antonioli E,Guglielmelli P,et al.Prospective identification of high-risk polycythemia vera patients based on JAK2(V617F)allele burden[J].Leukemia,2007,21(9):1952-1959.
[8]Passamonti F,Elena C,Schnittger S,et al.Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon12 mutations[J].Blood,2011,117(10):2813-2816.
[9]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.
[10]Nangalia J,Green AR.Myeloproliferative neoplasms:from origins to outcomes[J].Blood,2017,2017(1):2475-2483.
[11]Tefferi A,Rumi E,Finazzi G,et al.Survival and prognosis among 1 545patients with contemporary polycythemia vera:an international study[J].Leukemia,2013,27(9):1874-1881.
[12]Rampal R,Ahn J,Abdel-wahab O,et al.Genomic and functional analysis of leukemic transformation of myeloproliferative neoplasms[J].Proc Natl Acad Sci U S A,2014,111(50):E5401-E5410.
[13]Grinfeld J,Nangalia J.Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms[J].Haematologica,2017,102(1):7-17.
[14]Vannucchi AM,Verstovsek S,Guglielmelli P,et al.Ruxolitinib reduces JAK2 p.V617F allele burden in patients with polycythemia vera enrolled in the response study[J].Ann Hematol,2017,96(7):1113-1120.
[15]Bertozzi I,Bogoni G,Biagetti G,et al.Thromboses and hemorrhages are common in MPN patients with high JAK2V617F allele burden[J].Ann Hematol,2017,96(8):1-6.
[16]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.
[17]Bartels S,Faisal M,Büsche G,et al.Fibrotic progression in polycythemia vera is associated with early concomitant driver-mutations besides JAK2[J].Leukemia,2017,32(2):556-558.
[18]Tsuruta-Kishino T,Koya J,Kataoka K,et al.Loss of p53 induces leukemic transformation in a murine model of Jak2 V617F-driven polycythemia vera[J].Oncogene,2017,36(23):3300-3311.
[19]史仲珣,肖志坚.真性红细胞增多症诊断与治疗中国专家共识(2016年版)解读[J].中华血液学杂志,2016,37(10):852-857.
[20]Alvarez-Larrán A,Pereira A,Cervantes F,et al.Assessment and prognostic value of the European leukemia Net criteria for clinicohematologic response,resistance,and intolerance to hydroxyurea in polycythemia vera[J].Blood,2012,119(6):1363-1369.
[21]Passamonti F,Maffioli M.The role of JAK2 inhibitors in MPNs 7 years after approval[J].Blood,2018,131(5):2426-2435.
[22]Griesshammer M,Saydam G,Palandri F,et al.Ruxolitinib for the treatment of inadequately controlled polycythemia vera without splenomegaly:80-week follow-up from the response-2 trial[J].Ann Hematol,2018,97(5):1591-1600.
[23]Lussana F,Rambaldi A.Inflammation and myeloproliferative neoplasms[J].J Autoimmun,2017,(85):58-63.
[24]Passamonti F,Giorgino T,Mora B,et al.A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis[J].Leukemia,2017,(31):2726-2731.
[25]Lussana F,Rambaldi A,Finazzi MC,et al.Allogeneic hematopoietic stem cell transplantation in patients with polycythemia vera or essential thrombocythemia transformed to myelofibrosis or acute myeloid leukemia:a report from the MPN Subcommittee of the chronic malignancies working party of the european group for blood and marrow transplantation[J].Haematol,2014,99(4):916-921.
[26]Barbui T,Tefferi A,Vannucchi AM,et al.Philadelphia chromosomenegative classical myeloproliferative neoplasms:revised management recommendations from European Leukemia Net[J].Leukemia,2018,32(5):1057-1069.
[27]Bonicelli G,Abdulkarim K,Mounier M,et al.Leucocytosis and thrombosis at diagnosis are associated with poor survival in polycythaemia vera:a population-based study of 327 patients[J].Br JHaematol,2013,160(2):251-254.
[28]Tefferi A,Lasho TL,Guglielmelli P,et al.Targeted deep sequencing in polycythemia vera and essential thrombocythemia[J].Blood Adv,2016,1(2):21-30.
[29]Geyer H,Scherber R,Kosiorek H,et al.Symptomatic profiles of patients with polycythemia vera:Implications of inadequately controlled disease[J].J Clin Oncol,2016,34(2):151-159.
[30]Barbui T,Masciulli A,Marfisi MR,et al.White blood cell counts and thrombosis in polycythemia vera:a subanalysis of the CYTO-PV study[J].Blood,2015,126(4):560-561.