Evolution of Cytogenetically Normal Acute Myeloid Leukemia During Therapy and Relapse: An Exome Sequencing Study of 50 Patients
Evolution of Cytogenetically Normal Acute Myeloid Leukemia During Therapy and Relapse: An Exome Sequencing Study of 50 Patients
复制标题
DOI：
10.1158/1078-0432.ccr-17-2344
复制
发表时间：
2018-04-01
影响因子：
11.5
通讯作者：
Spiekermann, Karsten
中科院分区：
文献类型：
--
作者：
Greif, Philipp A.;Hartmann, Luise;Spiekermann, Karsten
目的：为了研究耐药性和疾病进展的机制，我们分析了细胞遗传学正常的急性髓性白血病（CN-AML）的演变的基础上体细胞alteration.Experimental设计：我们进行了外显子组测序匹配的诊断，缓解和复发样本50 CN-AML患者接受强化化疗。结果：突变模式与临床预后相关。突变的获得与晚期复发相关。表观遗传调节因子的改变经常在复发时获得，其中KDM 6A的反复改变构成阿糖胞苷耐药的机制。低KDM 6A表达与不良临床结局相关，尤其是在男性患者中。在完全缓解时，在48%的患者中观察到代表白血病前病变的持续突变。DNMT 3A突变的持续存在与复发时间的缩短相关。结论：化疗耐药可能是通过突变的获得而获得的。对治疗和疾病进展过程中演变的深入了解为治疗或预防CN-AML复发的定制方法奠定了基础。(C)2018年AACR。
Purpose: To study mechanisms of therapy resistance and disease progression, we analyzed the evolution of cytogenetically normal acute myeloid leukemia (CN-AML) based on somatic alterations.Experimental Design: We performed exome sequencing of matched diagnosis, remission, and relapse samples from 50 CN-AML patients treated with intensive chemotherapy. Mutation patterns were correlated with clinical parameters.Results: Evolutionary patterns correlated with clinical outcome. Gain of mutations was associated with late relapse. Alterations of epigenetic regulators were frequently gained at relapse with recurring alterations of KDM6A constituting a mechanism of cytarabine resistance. Low KDM6A expression correlated with adverse clinical outcome, particularly in male patients. At complete remission, persistent mutations representing preleukemic lesions were observed in 48% of patients. The persistence of DNMT3A mutations correlated with shorter time to relapse.Conclusions: Chemotherapy resistance might be acquired through gain of mutations. Insights into the evolution during therapy and disease progression lay the foundation for tailored approaches to treat or prevent relapse of CN-AML. (C) 2018 AACR.