单中心109例慢性粒-单核细胞白血病患者的分子学特征分析  

Molecular features of 109 patients with chronic myelomonocytic leukemia in a single center

作　　者：曲士强 潘丽娟 秦铁军 徐泽锋 李冰 王慧君 孙琦 贾玉娇 李承文 蔡文宇 高清妍 焦蒙 肖志坚 Qu Shiqiang;Pan Lijuan;Qin Tiejun;Xu Zefeng;Li Bing;Wang Huijun;Sun Qi;Jia Yujiao;LiChengwen;Cai Wenyu;Gao Qingyan;Jiao Meng;Xiao Zhijian(State Key Laboratory of Experimental Hematology,National Clinical Research Center for Blood Diseases,Haihe Laboratory of Cell Ecosystem,Institute of Hematology&Blood Diseases Hospital,Chinese Academy of Medical Sciences&Peking Union Medical College,Tianjin 300020,China;Tianjin Institutes of Health Science,Tianjin 301600,China)

机构地区：[1]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 [2]天津医学健康研究院,天津301600

出　　处：《中华血液学杂志》2023年第5期373-379,共7页Chinese Journal of Hematology

基　　金：国家自然科学基金(81530008、81870104);协和青年基金和中央高校基本科研业务费专项(3332019093);中国医学科学院医学与健康科技创新工程项目(2016-I2M-1-001、2020-I2M-C&T-A-020、2020-I2M-C&T-B-090、2022-12M-1-022)。

摘　　要：目的探索慢性粒-单核细胞白血病(CMML)的基因突变特征。方法按照WHO 2022分类,对2016年3月至2021年10月113例CMML和840例骨髓增生异常综合征(MDS)患者进行CMML重新诊断,并分析符合WHO 2022标准CMML患者的临床和分子学特征。结果113例WHO 2016标准诊断的CMML患者有23例(20.4%)重新诊断为急性髓系白血病(AML),包括18例AML伴NPM1突变,3例AML伴KMT2A重排和2例AML伴MECOM重排。另90例患者符合WHO 2022 CMML诊断标准。840例MDS患者中有19例(2.3%)符合WHO 2022 CMML诊断标准。99%的CMML患者检出至少1种基因突变,中位突变个数为4(2,5)个。突变检出率≥10%的基因依次为:ASXL1(48%)、NRAS(34%)、RUNX1(33%)、TET2(28%)、U2AF1(23%)、SRSF2(21.1%)、SETBP1(20%)、KRAS(17%)、CBL(16%)和DNMT3A(11%)。配对分析显示SRSF2同ASXL1(OR=4.129,95%CI 1.481~11.510,Q=0.007)和TET2(OR=5.276,95%CI 1.979~14.065,Q=0.001)常为共存突变。SRSF2和TET2常出现于老年(≥60岁)增殖型CMML(MP-CMML)患者。U2AF1同TET2(OR=0.174,95%CI 0.038~0.791,Q=0.024)常成互斥关系,易见于年轻(<60岁)发育异常型CMML(MDCMML)患者。单核细胞绝对值计数(AMoC)≥1×10^(9)/L和<1×10^(9)/L两组患者比较比较,前者有更高的中位发病年龄(60岁对47岁,P<0.001)、WBC(15.9×10^(9)/L对4.4×10^(9)/L,P<0.001)、单核细胞比例(21.5%对15%,P=0.001)和HGB水平(86 g/L对74 g/L,P=0.014)。TET2突变(P=0.021)和SRSF2突变(P=0.011)更常见于AMoC≥1×10^(9)/L组,而U2AF1突变(P<0.001)更常见于AMoC<1×10^(9)/L组。两组间的其他基因突变频率差异无统计学意义。结论按照WHO 2022分类,约20%的CMML病例诊断时的AMoC<1×10^(9)/L,MD-CMML和MP-CMML有不同的分子学特征。Objective To explore the molecular features of chronic myelomonocytic leukemia(CMML).Methods According to 2022 World Health Organization(WHO 2022)classification,113 CMML patients and 840 myelodysplastic syndrome(MDS)patients from March 2016 to October 2021 were reclassified,and the clinical and molecular features of CMML patients were analyzed.Results Among 113 CMML patients,23(20.4%)were re-diagnosed as acute myeloid leukemia(AML),including 18 AML with NPM1 mutation,3 AML with KMT2A rearrangement,and 2 AML with MECOM rearrangement.The remaining 90 patients met the WHO 2022 CMML criteria.In addition,19 of 840(2.3%)MDS patients met the WHO 2022 CMML criteria.At least one gene mutation was detected in 99%of CMML patients,and the median number of mutations was 4.The genes with mutation frequency≥10%were:ASXL1(48%),NRAS(34%),RUNX1(33%),TET2(28%),U2AF1(23%),SRSF2(21.1%),SETBP1(20%),KRAS(17%),CBL(15.6%)and DNMT3A(11%).Paired analysis showed that SRSF2 was frequently co-mutated with ASXL1(OR=4.129,95%CI 1.481-11.510,Q=0.007)and TET2(OR=5.276,95%CI 1.979-14.065,Q=0.001).SRSF2 and TET2 frequently occurred in elderly(≥60 years)patients with myeloproliferative CMML(MP-CMML).U2AF1 mutations were often mutually exclusive with TET2(OR=0.174,95%CI 0.038-0.791,Q=0.024),and were common in younger(<60 years)patients with myelodysplastic CMML(MD-CMML).Compared with patients with absolute monocyte count(AMoC)≥1×10^(9)/L and<1×10^(9)/L,the former had a higher median age of onset(60 years old vs 47 years old,P<0.001),white blood cell count(15.9×10^(9)/L vs 4.4×10^(9)/L,P<0.001),proportion of monocytes(21.5%vs 15%,P=0.001),and hemoglobin level(86 g/L vs 74 g/L,P=0.014).TET2 mutations(P=0.021)and SRSF2 mutations(P=0.011)were more common in patients with AMoC≥1×10^(9)/L,whereas U2AF1 mutations(P<0.001)were more common in patients with AMoC<1×10^(9)/L.There was no significant difference in the frequency of other gene mutations between the two groups.Conclusion According to WHO 2022 classification,nearly 20%of CMML patients h

关 键 词：慢性粒-单核细胞白血病 靶向测序 基因突变 

分 类 号：R733.72[医药卫生—肿瘤]