TET甲基胞嘧啶双加氧酶2基因突变对JAK2^(V617F)阳性骨髓增殖性肿瘤患者发生继发性骨髓纤维化的影响  

Effect of ten-eleven translocation methylcytosine dioxygenase 2 gene mutations on the secondary myelofibrosis of JAK2^(V617F) positive myeloproliferative neoplasms patients

作　　者：王艳 张宇卉 滕广帅[1] 杜晨霄 张会勤 段依璠 魏晓晶 马金玉 周圆 袁卫平 邵宗鸿 白洁 Wang Yan;Zhang Yuhui;Teng Guangshuai;Du Chenxiao;Zhang Huiqin;Duan Yifan;Wei Xiaojing;Ma Jinyu;Zhou Yuan;Yuan Weiping;Shao Zonghong;Bai Jie(Department of Hematology,the Second Hospital of Tianjin Medical University,Tianjin 300211,China;State Key Laboratory of Experimental Hematology,Institute of Hematology&Blood Diseases Hospital,National Clinical Research Center for Blood Diseases,Haihe Laboratory of Cell Ecosystem,Chinese Academy of Medical Sciences&Peking Union Medical College,Tianjin 300020,China)

机构地区：[1]天津医科大学第二医院血液科,天津300211 [2]中国医学科学院血液病医院(中国医学科学院血液学研究所)实验血液学国家重点实验室国家血液系统疾病临床医学研究中心细胞生态海河实验室,天津300020

出　　处：《中华医学杂志》2025年第3期219-224,共6页National Medical Journal of China

基　　金：国家自然科学基金(82270148);天津市教委科研计划(2022ZD072、2024KJ194)。

摘　　要：目的探讨TET甲基胞嘧啶双加氧酶2(TET2)基因突变对JAK2^(V617F)+骨髓增殖性肿瘤(MPN)患者发生继发性骨髓纤维化(SMF)的影响。方法回顾性收集天津医科大学第二医院血液科完成二代测序检测的JAK2^(V617F)突变的MPN患者,选取TET2基因突变的JAK2^(V617F)+MPN患者为突变组,年龄、性别相匹配的TET2基因未突变的JAK2^(V617F)+MPN患者为未突变组,随访至2022年11月11日,比较两组患者死亡率和SMF的差异。用二代测序技术检测血液系统肿瘤性疾病的325个突变基因,以确定两组突变基因的差异;酶联免疫吸附试验(ELISA)检测并比较2组患者骨髓上清转化生长因子(TGF)-β1、白细胞介素(IL)-17、干扰素(IFN)-γ等细胞因子水平的差异。采用多因素Cox回归模型分析JAK2^(V617F)+MPN患者发生SMF的影响因素。结果共纳入96例患者,突变组32例,男16例,女16例,年龄[M(Q1,Q3)]为61(53,70)岁;非突变组64例,男32例,女32例,年龄58(51,68)岁。共随访61(43,116)个月,突变组死亡率[15.6%(5/32)比1.6%(1/64),P=0.007]和SMF的比例[43.8%(14/32)比14.1%(9/64),P=0.001]均高于非突变组。突变组FAT1[25.0%(8/32)比7.8%(5/64),P=0.028]、U2AF1[15.6%(5/32)比0,P=0.003]、KMT2D[15.6%(5/32)比3.1%(2/64),P=0.039]基因突变的比例均高于非突变组。突变组TGF-β1[13837(8298,17509)比7915(3586,10545)ng/L,P=0.016]、IL-17[7.4(6.3,7.5)比6.1(5.9,7.1)ng/L,P=0.007]、IFN-γ[8.5(8.1,9.1)比8.0(7.5,8.3)ng/L,P=0.007]水平均高于非突变组。多因素Cox回归模型分析结果显示:TET2突变(HR=8.483,95%CI:1.278~56.330)是JAK2^(V617F)+MPN患者发生SMF的危险因素。结论TET2突变是影响JAK2^(V617F)+MPN患者发生SMF的危险因素。Objective To investigate the effect of ten-eleven translocation methylcytosine dioxygenase 2(TET2)gene mutations on the secondary myelofibrosis(SMF)of JAK2^(V617F)+myeloproliferative neoplasms(MPN)patients.Method A retrospective collection was conducted on MPN patients with JAK2^(V617F) mutation detected by second-generation sequencing in the Department of Hematology,the Second Hospital of Tianjin Medical University.TET2+JAK2^(V617F)+MPN patients were selected as the mutant group,and TET2-JAK2^(V617F)+MPN patients matched for age and gender were selected as the non-mutant group.The differences in mortality and SMF between the two groups were followed up until November 11,2022.The second-generation sequencing technology was used to detect 325 mutated genes in hematological malignancies,in order to determine the differences between two groups of mutated genes.Enzyme linked immunosorbent assay(ELISA)was used to detect and compare the levels of cytokines such as transforming growth factor(TGF)-β1,interleukin(IL)-17,interferon(IFN)-γ in the bone marrow supernatant of the both groups.Multivariate Cox regression analysis was used to investigate the influencing factors of SMF in JAK2^(V617F)+MPN patients.Result A total of 96 patients were included,with 32 in the mutant group,including 16 males and 16 females,aged[M(Q1,Q3)]61(53,70)years,and 64 in the non-mutant group,including 32 males and 32 females,aged 58(51,68)years.After a follow-up of 61(43,116)months,the mortality rate of patients in the mutant group[15.6%(5/32)vs 1.6%(1/64),P=0.007]and the proportion of SMF[43.8%(14/32)vs 14.1%(9/64),P=0.001]were higher than those in the non-mutant group.The proportion of FAT1[25.0%(8/32)vs 7.8%(5/64),P=0.028],U2AF1[15.6%(5/32)vs 0,P=0.003],and KMT2D[15.6%(5/32)vs 3.1%(2/64),P=0.039]gene mutations in the mutant group was higher than that in the non-mutant group.The mutant group had higher levels of TGF-β1[13837(8298,17509)vs 7915(3586,10545)ng/L,P=0.016],IL-17[7.4(6.3,7.5)vs 6.1(5.9,7.1)ng/L,P=0.007],and IFN-γ[8.5(8.1,9.1)vs

关 键 词：红细胞增多症 真性 原发性血小板增多症 TET2突变基因 细胞因子 

分 类 号：R733.3[医药卫生—肿瘤]