JAK2 V617F基因突变与脑梗死的相关性

<正>脑梗死占急性脑梗死的20%~30%〔1,2〕。JAK2 V617F基因突变为体细胞获得性单核苷酸突变,是由JAK2基因1 849位鸟嘌呤(G)突变为胸腺嘧啶(T),使JAK2蛋白617位缬氨酸错义编码为苯丙氨酸,导致JH2区的空间结构发生变化,使其对JH1区的抑制作用消失、JAK2激酶的活性增加〔3〕。JAK2V617F基因突变可出现在非典型慢性粒细胞性白血病、慢性粒     

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.     

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.     

骨髓增殖性肿瘤:从JAK2V617F突变到JAK抑制剂

<正>2005年在BCR-ABL(-)骨髓增殖性肿瘤(MPN)中发现JAK2V617F突变,使其从过去的近半个世纪几乎是一个被血液学界遗忘的角落重新回归研究视野〔1-3〕。2011年11月FDA批准第1个JAK抑制剂芦可替尼(ruxolitinib)用于IPSS中危-2和高危组原发性骨髓纤维化(PMF)患者的治疗。2013年12月2个研究组同时报道在无JAK2和MPL突变[JAK2/MPL(-)]的原发性血小板增多症(ET)和PMF患者中发现CALR基因     

A new era for IFN-α in the treatment of Philadelphia-negative chronic myeloproliferative neoplasms

In recent years, several studies have shown that IFN-?2 is able to induce molecular remissions with undetectable JAK2V617F in a subset of patients with essential thrombocythemia (ET) and polycythemia vera (PV), even with normalization of the bone marrow and sustained molecular remissions after discontinuation of IFN-?2. Accordingly, interest in using IFN-?2 in the treatment of patients with PV and related neoplasms has been revived. This article highlights the current status of IFN-?2 in the treatment of patients with ET, PV, primary myelofibrosis and myelofibrosis following ET and PV. In the context of being able to induce ?minimal residual disease? in a subset of patients after long-term treatment with IFN-?2, the current risk-stratification systems used for treatment decisions are being challenged. It is argued that in 2011, the bulk of evidence for the efficacy and safety of pegylated interferons in treating patients with these neoplasms favors the upfront use of pegylated interferons, the goal being to influence the development of the disease at the molecular level and revert patients to a stage of ?minimal residual disease/operational cure? instead of progressive clonal evolution, genomic instability and leukemic or myelofibrotic transformation during long-term treatment with hydroxyurea.     

原发性血小板增多症JAK2V617F点突变研究

2005年3月起多个研究组报道在原发性血小板增多症（ET）等bcr／abl阴性慢性骨髓增殖性疾病（CMPD）中存在JAK2基因点突变即JAK2V617F，为该病的发病机制、诊治带来了革命性进展。由于检测方法不同，检测到ET中该突变发生率为23％～57％。我们收集了45例ET患者的外周或骨髓血DNA，来探讨JAK2V617F阳性率及临床意义。     

JAK2V617F: better diagnostic tool than marrow?

In patients with Budd-Chiari syndrome and with portal vein thrombosis, Kiladjian et al observed that JAK2V617F positivity is indicative of the diagnosis of an underlying Ph1-negative myeloproliferative disorder, that is, polycythemia vera or essential thrombocytosis.     

JAK2V617F突变及JAK2激酶抑制剂对骨髓增殖性肿瘤的影响

<正>骨髓增殖性肿瘤(MPNs)是一类造血干细胞起源的骨髓克隆性疾病,是一种恶性血液系统疾病〔1〕。2008年,WHO论述的MPNs的详细列表包括慢性粒细胞白血病(CML),真性红细胞增多症(PV),原发性血小板增多症(ET),原发性骨髓纤维化(PMF),慢性中性粒细胞白血病(CNL),慢性嗜酸性粒细胞白血病/高嗜酸性粒细胞综合症(CEL/HES)和肥大细胞病(MCD)等疾病,并将有无JAK2突变列为重要的诊断标准〔2〕。近年来,JAK2激酶抑制剂对MPNs治疗的研究为MPNs患者带来了新的希望,也为临床使用JAK2V617F突变的基因靶向治疗提供了较好的实验依据。本文就至今为止JAK2V617F突变及JAK2激酶抑制剂对     

真性红细胞增多症患者JAK2V617F突变的临床意义

目的 探讨真性红细胞增多症(PV)患者JAK2V617F突变的临床意义.方法 用等位基因特异性PCR法检测26例PV、10例继发性红细胞增多症(SE)、5例Ph+慢性粒细胞白血病(CML)患者,以及5例健康志愿者的JAK2V617F突变,并经DNA测序验证.用PCR-限制性片段长度多态性分析检测JAK2V617F突变状态,分析突变状态与PV临床及实验室特征的关系.结果 PV患者92.3%(24例)出现JAK2V617F 突变,其中纯合子突变7例,杂合子突变17例;纯合子突变者初诊时Hb及乳酸脱氢酶高于杂合子者(P＜0.05).SE、Ph+CML患者及健康志愿者均未检出JAK2V617F突变.结论 JAK2V617F 突变可能成为PV的分子学诊断标准.     

JAK2 V617F阴性真性红细胞增多症患者JAK2 exon 12的突变研究

真性红细胞增多症(PV)是源于造血干细胞的克隆性骨髓增殖性疾病.2008年WHO正式将JAK2 V617F突变纳入了PV的诊断标准[1].但是临床上仍然有部分PV患者JAK2 V617F呈阴性,2007年Scott等[2]首次报道在这些病例中存在JAK2 exon 12突变,而目前国内尚无此方面的报道.为此我们对在山西医科大学第二医院就诊的JAK2 V617F阴性的PV患者进行JAK2 exon 12突变检测.     

MPN患者JAK2基因V617F点突变的检测及意义

目的探讨JAK2基因V617F点突变在骨髓增殖性肿瘤（MPN）中的发生情况及其意义。方法本组受检者共100例。MPN患者82例,其中真性红细胞增多症（PV）20例,有红细胞增多但未能诊断为PV者10例,原发性血小板增多症（ET）14例,有血小板增多但未能诊断为ET者13例,原发性骨髓纤维化（PMF）9例,慢性髓性白血病（CML）2例,其他MPN 6例,其他不明原因白细胞升高患者8例;另有急性白血病（AML）1例,骨髓增生异常综合征（MDS）10例、腔隙性梗死3例,慢性肾炎1例,大B细胞性淋巴瘤1例,异体胎肝移植患者1例,正常体检者1例。提取100例受检者外周血液及骨髓样本中有核细胞DNA,采用直接测序法进行JAK2第12、14外显子突变热点的检测。结果 100例样本中,有52例检测了第12、14两个外显子,48例仅检测第14外显子。未发现第12外显子突变。V617F及其他突变总检出率为38%（38/100）。PV、ET、PMF、CML、其他MPN、其他不明原因白细胞升高患者中均检测到不同比例的JAK2基因V617F点突变;而18例非MPN患者样本中均未发现V617F点突变,两组相比,P〈0.01。结论 JAK2基因突变在MPN的发生率高于其他血液疾病,可作为诊断MPN的一项重要参考指标。     

Is JAK2V617F Mutation the Only Factor for Thrombosis in Philadelphia-Negative Chronic Myeloproliferative Neoplasms?

The most common genetic disorder in Philadelphia negative chronic myeloproliferative neoplasms is the JAK2-V617F mutation. In the present study, we aimed to determine risk factors for thrombosis in patients with essential thrombocytosis and polycythemia vera. We screened the medical records of 101 patients. Risk factors which may predict thrombosis were recorded. Venous thrombosis (VT) before diagnosis was significantly higher in JAK2 positive patients. VT after diagnosis was similar in JAK2 positive and negative groups, and was significantly higher in elderly patients. Treatment places importance on the JAK2 mutation under unmodifiable cardiovascular risk factors such as advanced age after diagnosis.     

Primary thrombophilia in México VII: the V617F mutation of JAK2 is not a frequent cause of thrombosis

The study of the V617F JAK2 gene mutation has been used to identify the presence of an underlying myeloproliferative disorder (MPD) as the cause of unexplained thrombosis. In a group of 77 consecutive Mexican patients with a clinical marker of a primary thrombophilic condition, we looked for this JAK2 mutation and did not find any individual displaying it. Given these results, we conclude that an undetected MPD is a very improbable cause of thromboses in Mexican mestizos, a population where the prevalence of these disorders has been found to be lower than that found in Caucasian populations. Accordingly, it seems that the investigation for the V617F mutation of the JAK2 gene is not mandatory in all Mexican mestizo patients with unexplained thrombophilia and that this genetic study should be reserved for special cases, such as patients with thrombosis in uncommon sites or patients with cell counts suggesting the presence of an underlying MPD.     

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。     

dFARMS检测原发性血小板增多症JAK2基因V617F突变的研究

目的:对bcr/abl融合基因阴性的原发性血小板增多症(ET)患者进行JAK2V617F突变检测和相对定量,探讨敏感性高的检测方法,为临床诊断和预后判断提供依据.方法:用RT-PCR对28例ET患者进行bcr/abl融合基因检测;用双荧光扩增受阻突变系统(double fluorescent amplification refractory mutation system ,dFARMS)检测JAK2基因V617F突变,并对突变拷贝数行相对定量.结果:28例患者bcr/abl融合基因均阴性.dFARMS-PCR后,产物经普通琼脂糖凝胶电泳示JAK2V617F突变检出率为57.1%;产物经毛细管电泳示JAK2V617F突变检出率为67.9%.dFARMS检测的敏感性为0.01%.19例突变阳性患者,10例出现并发症,突变相对定量示高拷贝数,9例阴性患者无并发症出现.结论:dFARMS检测JAK2V617F突变敏感性高,特异性强,可用于临床检测,尤其对突变细胞数少的ET患者;携带有JAK2V617F突变及高突变拷贝数的ET患者,可能易出现并发症.     

JAK2 V617F 突变相关多发性腹腔静脉血栓合并门静脉炎1例

<正> 病例:患者男,68岁,因"门静脉高压2年余,脾切除术后2周余,发热1周"入院。患者40年前曾诊断为慢性乙型肝炎,ALT1000 U/L,中药保肝治疗3年余后肝功能恢复正常,之后未再复查肝炎指标。患者既往有铅接触史1年余,无饮酒史。1年半前,患者体检行B超检查示肝弥漫性病变、脾大,门静脉高压。盆腹部增强CT+血管重建示肝左静脉显示清晰,肝中、肝右静脉显示欠清;门静脉形态变异,左支于近段分为两支,右支近段瘤样扩张,远端纤细。血常规和肝肾功能均正常,HBsAg、HBV-DNA定量和HCV抗体均(-)。因患者无临床症状,故未行进一步诊治。2009年5月16日,患者无明显诱因下出现不完全性肠梗阻,予禁食、禁水、胃肠减压和抗感染治疗后症状缓解。查血常规和肝肾功能均正常,HBsAg、HCV抗体均(-);凝血功能检查示凝血酶原时     

Is the absence of JAK2V617F mutation a risk factor for bleeding in essential thrombocythemia? An analysis of 106 patients

Background

JAK2^V617F mutation has been recognized as a possible thrombotic risk factor in essential thrombocythaemia (ET). It’s role is probably due to an increased myeloid proliferation and white blood cells (WBC) activation. Only few data are available about the effect of JAK2^V617F on hemorrhagic risk. The aim of our study was to evaluate the influence of the mutational status on hemorrhagic complication.

Methods

We retrospectively analysed laboratory and clinical findings of 106 consecutive patients with ET to evaluate possible relationships between thrombosis, abnormal bleeding, peripheral blood count, overexpression of PRV1 and JAK2^V617F mutational status.

Results

On univariate analysis we found: an association between JAK2^V617F mutation and thrombotic events before or at diagnosis (p<0.003, OR=4.44, 95% CI=1.74–12.4); no statistical correlation between the median value of JAK2^V617F burden and an increased risk of thrombosis (p=0.4, 95% CI= −22.8–10.4); significant relationships between mutated status and higher haematocrit, high WBC count and low platelet count; and a strong correlation between JAK2^V617F and PRV1 overexpression (p<0.0001). Moreover, the presence of the JAK2^V617F mutation and a WBC count greater than 8.4 × 10⁹/L were found to be independent factors related to thrombotic complications in multivariable analysis (p<0.006, OR=3.85, 95% CI=1.3–11.9; and p<0.002, OR=2.8, 95% CI=1.08–7.03, respectively). The prognostic impact of JAK2 mutation status and WBC count on thrombosis was evaluated in the whole cohort. Only new cases occurring in patients without previous thrombotic events were recorded for the analysis. The multivariable analysis showed a statistical correlation between the presence of the mutation and a WBC count greater than 8.12 × 10⁶/L and an increased risk of thrombosis if no cytoreductive treatment was started at diagnosis (JAK2^V617F p=0.02; WBC p=0.02; OR=4.97; 95% CI=1.04–23.8). Finally, wild-type JAK2 was associated with a higher haemorrhagic risk (p=0.02) in univariate analysis but only a platelet count greater than 1,022 × 10⁹/L was associated with an increased risk of bleeding in the multivariable analysis.

Conclusion

Our data confirm the role of both JAK2^V617F as factor associated with an increased risk of thrombosis at the diagnosis and during follow-up in no treated patients. Moreover a WBC count over 8.4×10⁹/L¹ was also strictly associated to an increased risk of thrombosis. Regarding bleedings, our statistical analysis allows to exclude the mutation protective role on haemorrhage.