87例骨髓增殖性肿瘤患者JAK2及MPL基因突变位点研究

目的:探讨JAK2V617F及MPLW515L/K点突变在骨髓增殖性肿瘤(MPN)患者中的发生情况及临床意义。方法:回顾性统计分析87例MPN患者的临床及实验室检查资料,应用等位基因特异性-聚合酶链反应(AS-PCR)及序列测定方法,检测MPN患者骨髓/外周血单个核细胞JAK2V617F及MPLW515L/K点突变的发生情况,结合JAK2V617F及MPLW515L/K点突变阳性与阴性2组患者的临床及实验室检查指标,探讨其在疾病诊断及分子发病机制中的意义。结果:87例MPN患者[真性红细胞增多症(PV)36例,原发性血小板增多症(ET)33例,原发性骨髓纤维化(PMF)18例]中共检出55例患者存在JAK2V617F突变,总突变率为63.2%(55/87),其中PV28例,突变率77.8%(28/36);ET17例,突变率51.5%(17/33);PMF10例,突变率55.6%(10/18)。JAK2V617F阳性PV和ET患者WBC及Hb水平高于阴性患者(P<0.05);JAK2V617F阳性PMF患者WBC及PLT高于阴性患者(P<0.05)。JAK2V617F阳性MPN患者血栓发生率高于阴性患者(P<0...     

JAK2V617F基因突变与骨髓增殖性肿瘤关系

长期以来,除慢性髓系白血病的发病与BCR-ABL融合基因有关外,其他骨髓增殖性肿瘤(MPNs)的发病机制仍不清楚,近年来大量研究证实,在多种MPNs中存在较高的JAK2基因突变率,并认为该突变可能是BCR-ABL阴性MPNs所特有的分子标志.该文就近年来对JAK2基因突变、MPNs的最新诊断和靶向治疗等方面的研究进展进行综述.     

JAK2V617F突变背景下骨髓增殖性肿瘤临床表型异质性的研究进展

［摘要］　费城染色体阴性骨髓增殖性肿瘤(MPNs)是一组以造血干细胞克隆性增殖为主要特征的慢性血液肿瘤。JAK2V617F突变常见于MPNs,是诊断标准之一,其通过突变频率影响MPNs表型异质性。此外,信号通路、表观遗传学修饰、免疫异常、生活方式和其他一些因素也参与JAK2V617F相关的MPNs的异质性。该文对JAK2V617F影响MPNs表型的研究进展作一综述。     

JAK2V617F点突变在BCR-ABL阴性骨髓增殖性疾病中的意义

目的研究JAK2V617F点突变在诊断BCR—ABL融合基因阴性的骨髓增殖性疾病（MPD）患者中的意义。方法选择51例BCR—ABL阴性MPD患者,采用等位基因特异PCR法检测各组患者JAK2V617F的突变情况。结果51例BCR—ABL融合基因阴性的MPD患者中,34例JAK2V617F突变阳性,其中原发性血小板增多症（ET）18例（69．23％）,真性红细胞增多症（PV）16例（66．67％）,特发性骨髓纤维化（IMF）1例为阴性;PV与ET患者相比更容易发生肝脾肿大、脑梗死、静脉血栓形成、高尿酸血症等并发症（P〈0．05）。ET患者中,JAK2V617F突变阳性组白细胞计数较阴性组高（P〈0．05）。ET患者中,JAK2V617F突变阳性组白细胞计数较阴性组高（P〈0．05）,ET和PV患者中JAK2V617F突变阳性组都比阴性组更容易发生上述并发症等（P均〈0．05）。结论JAK2V617F点突变在BCR—ABL融合基因阴性MPD中有较高的发生率,具有明确的诊断学意义;ET及PV患者中此突变阳性者更易发生血栓形成等并发症。     

慢性淋巴细胞白血病合并骨髓增殖性肿瘤临床特征分析

目的 探究慢性淋巴细胞白血病(CLL)和骨髓增殖性肿瘤(MPN)共患病可能的发病机制并分析其临床特征。方法 回顾性纳入2000年～2020年世界范围内报道的CLL合并MPN患者112例及本院CLL合并MPN患者1例。根据MPN类型将所有患者分为真性红细胞增多症(PV)合并CLL组(35例)、原发性血小板增多症(ET)合并CLL组(53例)及原发性骨髓纤维化(PMF)合并CLL组(25例);根据JAK2V617F突变情况将已知突变情况患者95例,分为JAK2V617F阳性组(66例)和JAK2V617F阴性组(29例);根据疾病诊断顺序将所有患者分为先MPN后CLL组(60例)、同时诊断组(27例)及先CLL后MPN组(26例)。收集所有患者性别、诊断年龄、两种疾病诊断间隔时间、疾病诊断类型、JAK2V617F突变情况及其他类型突变情况、治疗及转归情况、存活状态、生存时间、MPN类型、疾病诊断顺序等临床特征资料并分组进行比较。结果 3个MPN合并CLL组中共患病以ET合并CLL最为常见(46.9%)。PV合并CLL组JAK2V617F阳性患者比例明显高于其他两组(P<0.05)。P...     

JAK2V617F基因突变阳性骨髓增殖性肿瘤相关门静脉海绵样变性1例

<正>骨髓增殖性肿瘤(myeloproliferative neoplasms,MPN)导致血细胞增加、血液高凝,是非肝硬化门静脉海绵样变性的重要病因。JAK2V617F基因突变可以帮助诊断MPN。我们报道1例JAK2V617F基因突变阳性的MPN患者发生门静脉海绵样变性(cavernous transformation of the portal vein,CTPV)。该例患者脾脏显著肿大,一方面是由于骨髓增殖性疾病本身的原因,另一方面是由于PVCT、门脉高压和脾脏淤血造成,表现为外周血血细胞计数基本在正常范围,亦是血细胞增殖和脾脏对血细胞的处理增加的共同作用的结果。抗凝治疗效果差,而应以预防食管曲张静脉破裂出血(EVB)为主。     

骨髓增殖性肿瘤128例JAK2V617F基因突变与血栓栓塞关系研究

目的研究骨髓增殖性肿瘤(MPN)患者JAK2V617F突变与发生血栓栓塞的关系。方法回顾性分析2008年2月至2011年7月新疆地区128例不同民族MPN患者临床特征、实验室检查、JAK2V617F基因突变及血栓栓塞事件发生情况等资料。结果 MPN患者中93例(72.6%)存在JAK2V617F突变,66例(51.6%)发生血栓事件,其中突变阳性93例患者中58例有血栓形成,35例突变阴性患者中8例有血栓形成,突变阳性组与阴性组血栓发生率比较差异有统计学意义(χ2=15.893,P<0.05)。76例汉族MPN中58例为突变阳性,42例发生血栓,52例少数民族中35例突变阳性,24例发生血栓,汉族与少数民族患者JAK2基因突变总阳性率及血栓发生率比较均无统计学意义(χ2=1.261,1.026,P>0.05)。结论真性红细胞增多症、原发性血小板增多症及特发性骨髓纤维化等经典MPN患者中均有较高的JAK2V617F基因突变率,并突变阳性者血栓发生率明显高于阴性者;新疆地区汉族与维、哈、回等少数民族MPN患者JAK2V617F基因突变阳性率及血栓形成率之间差异无统计学意义。该突变阳性、年龄≥60岁、WBC≥15×109/L、合并有血管危险因素的患者血栓发生风险可能会高,应尽早予以干预治疗。     

吉林地区深静脉血栓患者JAK2V617F突变

目的 探讨吉林地区深静脉血栓患者JAK2V617F突变情况.方法 应用等位基因特异性PCR检测50例深静脉血栓患者外周血基因组DNA中是否存在JAK2V617F突变.结果 50例深静脉血栓患者中均未检出JAK2V617F突变.结论 JAK2V617F突变在吉林地区深静脉血栓患者中不存在或发生率很低,可能不是引起吉林地区深静脉血栓疾病的原因.     

骨髓增殖性疾病137例患者JAK2基因突变的研究

目的探讨信号分子JAK2基因突变——JAK2V617F在骨髓增殖性疾病（MPD）患者中的发生情况及诊断价值。方法采用等位基因特异性PCR方法及序列测定,检测137例MPD患者骨髓及外周血单个核细胞JAK2基因第12号外显子,研究JAK2V617F的发生情况,并结合细胞遗传学及分子生物学等检查结果分析其诊断价值。结果137例MPD患者共检出90例JAK2V617F阳性,总阳性率65．7％;其中真性红细胞增多症（PV）57例,阳性率73．7％（42／57）;原发性血小板增多症（ET）68例,阳性率58．8％（40／68）;特发性骨髓纤维化（IMF）12例,阳性率66．7％（8／12）;PV及ET患者突变型平均年龄高于野生型（P〈0．05）。115例进行过染色体检查,其中7例存在核型异常,突变型5例,阳性率为71．4％（5／7）;染色体核型正常者108例,突变型74例,阳性率68．5％;两组差异无统计学意义。结论MPD患者中JAK2V617F发生率较高,其发生与年龄相关,突变型平均年龄高于野生型。     

Molecular testing for JAK2, MPL,and CALR in myeloproliferative neoplasms

Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are myeloproliferative neoplasms characterized by recurrent somatic mutations in JAK2, CALR, and MPL. This short review addresses (1) the spectrum of mutations seen in PV, ET, and PMF, (2) the emerging genotype‐phenotype correlations, (3) the current role of molecular testing in disease classification and management, and (4) several important considerations for selecting an appropriate molecular test. In our view, sequential testing algorithms and simultaneous assessment of multiple mutations by next‐generation sequencing are both valid approaches to testing. Am. J. Hematol. 91:1277–1280, 2016. © 2016 Wiley Periodicals, Inc.     

CALR,JAK2 and MPL mutation status in Argentinean patients with BCR-ABL1- negative myeloproliferative neoplasms

Objectives: To establish the frequency of JAK2, MPL and CALR mutations in Argentinean patients with BCR-ABL1-negative myeloproliferative neoplasms (MPN) and to compare their clinical and haematological features.

Methods: Mutations of JAK2V617F, JAK2 exon 12, MPL W515L/K and CALR were analysed in 439 Argentinean patients with BCR-ABL1-negative MPN, including 176 polycythemia vera (PV), 214 essential thrombocythemia (ET) and 49 primary myelofibrosis (PMF).

Results: In 94.9% of PV, 85.5% ET and 85.2% PMF, we found mutations in JAK2, MPL or CALR. 74.9% carried JAK2V617F, 12.3% CALR mutations, 2.1% MPL mutations and 10.7% were triple negative. In ET, nine types of CALR mutations were identified, four of which were novel. PMF patients were limited to types 1 and 2, type 2 being more frequent.

Discussion: In ET, patients with CALR mutation were younger and had higher platelet counts than those with JAK2V617F and triple negative. In addition, JAK2V617F patients had high leucocyte and haemoglobin values compared with CALR-mutated and triple-negative patients. In PMF, patients with mutant CALR were associated with higher platelet counts.

Conclusion: Our study underscores the importance of JAK2, MPL and CALR genotyping for accurate diagnosis of patients with BCR-ABL1-negative MPN.     

JAK2 and MPL mutations in myeloproliferative neoplasms

The Philadelphia chromosome-negative myeloproliferative disorders (MPDs) polycythemia vera (PV), essential thrombocytosis (ET) and primary myelofibrosis (PMF) are characterized by increased proliferation of terminally differentiated myeloid cells. Although these disorders were recognized as clonal hematopoietic stem cell disorders more than 3 decades ago, little was known about the genetic basis for these disorders until 2005 when a single recurrent mutation in the JAK2 tyrosine kinase (JAK2V617F) was identified in >90% of patients with PV and in a significant proportion of patients with ET and PMF. JAK2V617F is a constitutively active tyrosine kinase and has transforming properties in vitro and in vivo, providing validation JAK2V617F is a bona fide oncogene which contributes to MPD pathogenesis. Subsequent studies of JAK2V617F-negative MPDs have identified mutations in JAK2 exon 12 and MPL, and these mutations also result in constitutive activation of JAK2 signaling. In this review, we will discuss the genetics of PV, ET and PMF with regard to known somatic mutations, the role of these mutations in hematopoietic transformation and the therapeutic implications of these findings.     

JAK2, MPL,and CALR mutations in Chinese Han patients with essential thrombocythemia

Background: Mutations in Janus kinase 2 (JAK2), myeloproliferative leukemia (MPL), and CALR are highly relevant to Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms.

Methods: Assessing the prevalence of molecular mutations in Chinese Han patients with essential thrombocythemia (ET), and correlating their mutational profile with disease characteristics/phenotype.

Results: Of the 110 subjects studied, 62 carried the JAK2 V617F mutation, 21 had CALR mutations, one carried an MPL (W515) mutation, and 28 had non-mutated JAK2, CALR, and MPL (so-called triple-negative ET). Mutations in JAK2 exon 12 were not detected in any patient. Two ET patients had both CALR and JAK2 V617F mutations. Comparing the hematological parameters of the patients with JAK2 mutations with those of the patients with CALR mutations showed that the ET patients with CALR mutations were younger (p?=?0.045) and had higher platelet counts (p?=?0.043).

Conclusion: Genotyping for CALR could be a useful diagnostic tool for JAK2/MPL-negative ET, since the data suggest that CALR is much more prevalent than MPL, therefore testing for CALR should be considered in patients who are JAK2 negative as its frequency is almost 20 times that of MPL mutation.     

JAK2 GGCC haplotype in MPL mutated myeloproliferative neoplasms

JAK2 (V617F) is associated with a genetic predisposition to its acquisition,as it is preferentially found in subjects with a common constitutional JAK2 haplotype known as 46/1 or GGCC. A recent study suggests that a genetic predisposition to acquisition of MPL mutation may exist in sporadic patients, since an association was found with the JAK2 46/1 haplotype. We genotyped 509 patients with myeloproliferative neoplasms (MPN), 7% of which carrying a somatic mutation of MPL Exon 10. We found that the JAK2 GGCC haplotype was closely associated with JAK2 (V617F) (OR 1.84, P < 0.001) but not with MPL mutations (OR 0.98), suggesting a different genetic background for these molecular lesions.     

Prognostic value of JAK2, MPL and CALR mutations in Chinese patients with primary myelofibrosis

<正>Objective To evaluate the prognostic value of JAK2,MPL and CALR mutations in Chinese patients with primary myelofibrosis(PMF).Methods Four hundred and two Chinese patients with PMF were retrospectively analyzed.The Kaplan-Meier method,the Log-rank test,the likelihood ratio test and the Cox proportional     

Detection of MPL exon10 mutations in 103 Chinese patients with JAK2V617F-negative myeloproliferative neoplasms

JAK2V617F mutation has been reported in 90% of patients with polycythemia vera (PV) and about 50% of patients with essential thromobocythemia (ET) and primary myelofibrosis (PMF). Recently, acquired mutations in the transmembrane-juxtamembrane region of MPL (MPLW515 mutations) have been reported in approximately 5% of JAK2V617F-negative PMF and about 1% of all cases of ET. MPL is the receptor for thrombopoietin that regulates the production of platelets by bone marrow. It is likely that some mutations more closely related to ET in MPL exon10 may have been missed by current assays. We inferred that there might be other mutations in MPL exon10 for MPN patients in addition to MPLW515 mutations. To investigate its mutation types and prevalence in Chinese patients with myeloproliferative neoplasms (MPN), we performed mutation detection on MPL exon10 in 103 JAK2V617F-negative MPN patients by single strand conformation polymorphism (SSCP) and allele-specific PCR (AS-PCR) combined with sequencing. As a result, one previously unrecognized MPL mutation (12-bp in-frame insertion) was identified in one patient with ET in addition to an MPLW515K mutation identified in one PMF patient. This confirms our hypothesis that BCR/ABL negative and JAK2V617F-negative MPN patients have other mutations besides W515 mutation in MPL exon10 and mutations other than single nucleotide exchange also exist. In addition, MPL mutation was associated with Chinese MPN patients.