骨髓增殖性肿瘤CALR基因突变的研究进展

骨髓增殖性肿瘤(MPN)是一类以一系或多系髓系细胞增殖为主要特征的克隆性造血干细胞疾病,分为bcr-abl融合基因阳性的慢性粒细胞白血病和bcr-abl阴性MPN,后者主要包括真性红细胞增多症(PV)、原发性血小板增多症(ET)和原发性骨髓纤维化(PMF)3种经典类型.随着JAK2、MPL等突变基因的不断发现,对这类疾病的认识有了巨大进展.但JAK2/MPL突变双阴性MPN患者的遗传学基础仍不完全清楚.近年研究发现JAK2/MPL未突变的MPN患者获得新的CALR突变,且该类患者表现出明显不同的临床特征,为疾病诊断和预后评价提供了一个新的分子标准.文章就CALR基因突变的发现及其介导MPN发生的机制研究等作一综述.     

A novel p27 gene mutation in a case of unclassified myeloproliferative disorder

P27 encodes a member of Cip/Kip family of cyclin dependent kinase inhibitors, the inactivation of which has been implicated in the pathogenesis of various hematological neoplasias. We report on a novel point mutation of this gene identified in a case of unclassified myeloproliferative syndrome consisting of a T --> C transversion at 821bp of p27 exon 1, resulting in a Ile --> Thr substitution at codon 119. The analysis of larger number of cases as well as the effect of this mutation on protein's function will help to clarify its significance in the pathogenesis of myeloproliferative syndromes.     

Serum beta 2-microglobulin in lymphoproliferative and myeloproliferative diseases

The serum levels of beta 2-microglobulin (beta 2m), which is the light chain moiety of the HLA (-A, -B, -C) antigens, are increased in many of the haematological malignancies. In the lymphoproliferative disorders there is generally an association between serum beta 2m and estimates of tumour load. This relationship is especially close in myelomatosis, where serum beta 2m is a powerful prognostic indicator and can be used in stratification and monitoring. Increases in serum beta 2m are also frequent in the myeloproliferative disorders, notably in myelofibrosis, and in the myelodysplastic syndromes; particularly high levels are seen in chronic myelomonocytic leukaemia. In addition to suggested cellular sources of the beta 2m in these diseases--malignant lymphoid cells and cells of the monocyte-macrophage series--the possibility that T lymphocyte sub-sets could be important contributors to the increased beta 2m production is discussed.     

骨髓增殖性肿瘤患者蛋白酪氨酸磷酸酶1B基因突变分析

目的 分析骨髓增殖性肿瘤(MPN)患者中蛋白酪氨酸磷酸酶1B(PTP1B)基因突变情况.方法 采用DNA测序技术检测84例MPN患者及37例健康对照者PTP1B的DNA序列.结果 MPN患者及健康对照者均未检测到Exon1 ～6、Exon9和Exon10突变.MPN患者中有18例检测到Exon8 C/T杂合性突变,健康对照者中有10例检测到C/T杂合性突变,两组之间差异无统计学意义(x 2=0.453,P=0.501).38例患者进行了Exon7基因测序,2例有C/T杂合性突变,健康对照者中有1例G/C杂合性突变.所有受试者均未检测到纯合性突变.结论 MPN患者PTP1B基因突变与健康对照者相比没有明显差异.     

Dysregulation of the protein tyrosine kinase LCK in lymphoproliferative disorders and in other neoplasias

Initially identified as a T-cell specific member of the Src family of protein tyrosine kinases, Lck has become the object of intensive investigations which have revealed a key role for this kinase in the central processes controlling T-cell development, activation, proliferation and survival. Experimental evidence of the oncogenic potential of Lck, together with the identification of defects in the regulation of Lck expression or activity in T-cell leukemias, suggests that dysregulation of Lck might play a role in neoplastic transformation. Here we review the data documenting a potential role for this kinase in the initiation and maintenance of the transformed state in human cancers.     

Coincidence of a myeloproliferative and a lymphoproliferative disorder--a random event?

A patient with coinciding polycythemia vera and chronic lymphocytic leukemia is reported. Based on a literature review and vital statistics it is concluded that the coincidence is probably fortuitous.     

bcr-abl阴性骨髓增殖性肿瘤患者基因突变及合并血栓的危险因素分析

目的 探讨bcr-abl阴性骨髓增殖性肿瘤(MPN)JAK2 V617F、JAK2(exon12)、CALR和MPL基因突变与患者临床特征的关系,并分析发生血栓的危险因素.方法 回顾性分析115例bcr-abl阴性MPN患者初诊时的临床特征和实验室指标.34例发生血栓事件的患者为观察组,81例未发生血栓事件的患者为对照组,分析影响患者发生血栓事件的危险因素.结果 在71例原发性血小板增多症(ET)患者中,JAK2 V617F阳性组、CALR阳性组的白细胞计数(WBC)、血红蛋白(Hb)水平与4种突变均阴性组比较,差异有统计学意义(F=5.835,P=0.005;F=3.405,P=0.039);JAK2 V617F阳性组、CALR阳性组的脾大发生率高于4种突变均阴性组(χ2=16.902,P=0.0002;χ2=12.658;P=0.001).观察组中JAK2 V617F阳性、高Hb水平(男性≥160 g/L,女性≥150 g/L)、合并高血压、年龄≥60岁患者所占比例高于对照组(χ2=5.585,P=0.025;χ2=4.909,P=0.043;χ2=8.891,P=0.004;χ2=15.933,P=0.023).结论 检测JAK2 V617F、JAK2(exon12)、CALR和MPL基因突变有助于bcr-abl阴性MPN患者的诊断;JAK2 V617F阳性、高Hb水平、高血压、高龄是发生血栓的危险因素.     

JAK2 V617F基因突变阳性骨髓增殖性肿瘤治疗研究进展

JAK2 V617F基因突变阳性骨髓增殖性肿瘤(MPN)由真性红细胞增多症(PV)、原发性血小板增多症(ET)和原发性骨髓纤维化(PMF)组成.文章聚焦于其危险度积分系统和治疗进展,包括一线及二线治疗、JAK2抑制剂、降细胞治疗、抗纤维化和其他单药或联合治疗.     

BCR-ABL阴性骨髓增殖性肿瘤JAK2 V617F基因突变状态及负荷的临床意义

目的探讨JAK2 V617F基因突变状态及负荷对BCR-ABL阴性骨髓增殖性肿瘤(MPN)的影响。方法回顾性分析2015年9月至2020年1月河北省沧州市中心医院199例MPN患者的临床资料。分析JAK2 V617F突变负荷与MPN患者临床病理特征及预后评分的关系。结果199例BCR-ABL阴性MPN患者中JAK2 V617F突变阳性138例(69.4%);其中,72例真性红细胞增多症(PV)患者中突变阳性64例(88.9%),101例原发性血小板增多症(ET)患者中突变阳性54例(53.5%),25例骨髓纤维化(MF)患者中突变阳性20例(80.0%),1例嗜酸粒细胞增多症(HES)患者突变阳性。JAK2 V617F突变高负荷者占55.1%(76/138)。突变负荷最高的类型为PV,MF次之,ET最低,3组突变负荷分别为(73.9±18.3)%、(59.9±25.2)%、(25.0±16.5)%。JAK2 V617F突变负荷与PV、ET、MF患者的白细胞计数均呈正相关(r值分别为0.626、0.675、0.796,均P<0.01)。JAK2 V617F突变负荷与PV、ET患者的预后评分均呈正相关(r值分别为0.296、0.404,均P<0.05)。结论BCR-ABL阴性MPN患者JAK2 V617F突变负荷与临床病理因素相关,JAK2 V617F突变高负荷患者预后不良。     

Clinical and biological characteristics of cervical neoplasias with FGFR3 mutation

Background  

We have previously reported activating mutations of the gene coding for the fibroblast growth factor receptor 3 (FGFR3) in invasive cervical carcinoma. To further analyze the role of FGFR3 in cervical tumor progression, we extended our study to screen a total of 75 invasive tumors and 80 cervical intraepithelial neoplasias (40 low-grade and 40 high-grade lesions).     

骨髓增殖性肿瘤120例JAK2 V617F基因突变的临床分析

目的 探讨JAK2 V617F基因突变在骨髓增殖性肿瘤(MPN)患者中的发生率及临床意义.方法 采用骨髓细胞学和活组织检查方法分析120例患者的骨髓病理状况,监测费城染色体(Ph染色体)和bcr-abl融合基因.从患者骨髓抽提DNA,采用荧光定量PCR技术检测JAK2 V617F基因突变.结果 所有患者均呈现出MPN各自类型的典型特征.Ph染色体和bcr-abl融合基因检测均为阴性.120例MPN患者中JAK2 V617F基因突变的阳性率为66.7％(80/120),其中真性红细胞增多症(PV)为72.7％(16/22),原发性血小板增多症(ET)为66.0％(62/94),4例原发性骨髓纤维化(PMF)患者中2例阳性.JAK2 V617F突变阳性PV患者的外周血白细胞计数(P=0.001)和血小板计数(P=0.010)均高于阴性患者;JAK2 V617F突变阳性ET患者的白细胞计数高于阴性患者(P=0.006);PMF中JAK2V617F突变阳性和阴性患者间各项指标差异均无统计学意义(均P＞0.05).结论 JAK2 V617F基因突变检测有助于bcr-abl阴性MPN的诊断和鉴别诊断,使患者能够在早期被发现和治疗.     

The investigations of the cellular type of immunity in patients with lymphoproliferative and myeloproliferative diseases

Delayed hypersenstivity to streptokinase and tuberculin used as antigens, and the capacity to form antibodies to streptokinase, were investigated in various malignant blood diseases and the results were compared with those found in some other diseases and in a control group of healthy subjects. It was found that anergy similar to that seen in Hodgkin's disease (also confirmed in this work) can be found with regard to two antigens in reticulosarcoma, myeloma, acute leukaemia and chronic myelosis. In myelofibrosis partial anergy was observed only with streptokinase but not with tuberculin antigen. The anergy was in general not correlated with the absolute lymphocyte count in the peripheral blood nor with the treatment given. The increase in antistreptokinase antibodies after immunization with streptokinase was investigated. This administration of the antigen (secondary response) gave results which did not differ from those in controls in Hodgkin's disease, reticulosarcoma, acute leukaemia and chronic myelosis. In myeloma and especially in chronic lymphatic leukaemia, however, the antibody-forming capacity was significantly decreased. Thus, the results point to a dissociation in the immunological response: in Hodgkin's disease, reticulosarcoma, acute leukaemia and chronic myelosis, there is a significant decrease in the response of the cellular type with preservation of antibody-forming power. In myeloma both types of reactions are decreased. In chronic lymphatic leukaemia antibody-forming capacity is reduced with relatively good preservation of the cellular type of reactivity. Delayed hypersensitivity to tuberculin was also depressed in patients with sarcoidosis although tested during remission, whereas skin sensitivity to streptokinase was preserved. In patients with pancytopenia the delayed hypersensitivity was only slightly suppressed, but there was a tendency to produce higher antibody titres against streptokinase than in the controls, although the difference was not statistically significant. There were similar findings in patients with autoimmune haemolytic anaemia.     

A candidate gene for Drosophila genome methylation

Like vertebrates, the genome of Drosophila melanogaster also contains methylated cytosines. However, the enzyme(s) responsible for this methylation has been elusive. By DNA transfection and sodium bisulfite sequencing, we show here that overexpression of dDnmt2, which is the only expressed and cloned Drosophila protein consisting of motifs conserved among the DNA cytosine methyltransferases, results in genomic DNA methylation of Drosophila S2 cells. The data provide the first evidence for dDnmt2 being one candidate gene encoding the Drosophila DNA methyltransferase(s).     

候选抑癌基因RIZ1

视网膜母细胞瘤蛋白质结合的锌指蛋白1( RIZ1)是一种甲基转移酶,其功能单位为特征性的PR锌指结构域.RIZ1能够通过PR结构域甲基化组蛋白3上第9位的赖氨酸,导致相应基因转录受抑,具有抑制肿瘤发生的作用.RIZ1在多种人类肿瘤中表达减低或缺失,其表达水平减低与肿瘤发生、进展等密切相关,被定义为一种候选抑癌基因.RIZ1在肿瘤中表达减低机制既涉及细胞遗传学又与表观遗传学改变密切相关.     

A high-throughput customized cytokinome screen of colon cancer cell responses to small-molecule oncology drugs

Inflammatory cytokines, chemokines, and growth factors are molecular messengers that circulate and have the capability to modify the tumor microenvironment and impact therapeutic response. The characterization of soluble mediators as biomarkers for diagnosis and prognosis is of interest in oncology. We utilize the cytokinome to characterize the response of colorectal tumor cell lines to selected small-molecules in oncology as a proof-of-concept dataset with immunomodulatory analyte heat map rankings for drug and cell line combinations. We observed overall trends in drug class effects with MEK-, BRAF-, PARP-inhibitors, and Imipridones in cytokine, chemokine, and growth factor responses that may help guide therapy selection. MEK-inhibitor treatment downregulated analytes VEGF, CXCL9/MIG, and IL-8/CXCL8 and upregulated CXCL14/BRAK, Prolactin, and CCL5/RANTES. BRAF-inhibitor treatment downregulated VEGF and IL-8/CXCL8, while increasing soluble TRAIL-R2. Treatment with PARP-inhibitors decreased CXCL9/MIG, IL-8/CXCL8, CCL3/MIP-1 alpha, VEGF, and CXCL14/BRAK, while treatment increased soluble TRAIL-R2 and prolactin. Treatment with Imipridones decreased CCL3/MIP-1 alpha, VEGF, CXCL14/BRAK, IL-8/CXCL8, and Prolactin and increased CXCL5/ENA-78. We also observed differential responses to therapeutics depending on the mutational profile of the cell line. In the future, a similar but larger dataset may be utilized in the clinic to aid in the prediction of patient response to immunomodulatory therapies based on tumor genotype.     

实时定量聚合酶链反应检测慢性骨髓增殖性疾病患者JAK2 V617F基因突变

 目的　观察实时定量聚合酶链反应（PCR）检测慢性骨髓增殖性疾病（CMPD）中JAK2基因V617F点突变情况。方法　采用实时定量PCR法检测56例CMPD患者JAK2 V617F基因突变类型及突变转录水平。其中,真性红细胞增多症（PV）26例、原发性血小板增多症（ET）24例、原发性骨髓纤维化（CIMF） 5例、高嗜酸粒细胞综合征（HES）1例。结果　56例CMPD患者JAK2 V617F基因突变率为51.79 ％（29／56）,PV 65.38 %（17／26）、ET 37.50 %（9／24）、IMF 60.00 %（3／5）;杂合性突变率为41.07 %（23／56）,包括PV 53.85 %（14／26）、ET 29.17 %（7／24）、CIMF 40.0 %（2／5）;纯合性突变率为10.71 %（6／56）, 包括PV 11.54 %（3／26）、ET 8.33 %（2／24）、CIMF 20.00 %（1／5）;1例HES患者为野生型。PV、ET和CIMF突变患者拷贝数分别为2.14×102～1.5×107、9.80×102～4.4×107和4.10×103～3.70×106。结论　实时定量PCR检测JAK2 V617F基因简便、快捷, 并且易于定量, 检测阳性率与国外报道相似, 适合临床用于CMPD的诊断和疗效评估。