急性白血病基因突变与多步骤发病机制和临床相关性  被引量:12

Gene Mutations in Multi-Step Pathogenesis in Acute Myeloid Leukemia and Their Clinical Relevance

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作  者:沈杨[1] 陈赛娟[1] 

机构地区:[1]上海交通大学医学院附属瑞金医院,上海市血液学研究所,上海200025

出  处:《中国科学:生命科学》2013年第1期39-45,共7页Scientia Sinica(Vitae)

基  金:国家自然科学基金(批准号:30671538)资助项目

摘  要:急性髓细胞白血病(AML)是一组在发病机制和临床行为方面差异较大的疾病.在急性早幼粒细胞白血病中(APL),PML-RARα是APL的关键驱动(driver)突变,具有显性负的调控作用,影响髓系分化、凋亡和DNA复制和修复,其特殊结构使其成为全反式维甲酸和三氧化二砷的靶标.随着第二代测序技术的发展,在AML中发现了一些新的基因突变,其中DNA甲基转移酶3A(DNMT3A)突变是与表观遗传学相关的、与AML较差预后有关的基因事件.在1185例AML的基因分析中,研究发现与表观遗传学相关的第Ⅲ类突变与老年、高WBC及较差的临床预后有关.AML的发病是多步骤的,涉及不同通路上不同分子事件的相互作用,目前认为影响转录因子和信号传导通路的分子事件相互作用是AML完全发病的重要模式之一.Acute myeloid leukemia (AML) is a group of heterogeneous diseases varying in leukemogenesis and clinical behavior.In acute promyelocytic leukemia (APL), PML-RARa is the driver mutation leading to the development of the disease, which bears dominant negative regulation effect, influencing the myeloid differentiation, apoptosis and duplication and repair of DNA, and its individual structure makes it a specific target for ATRA and arsenic trioxide. With the development of second generation sequencing technology, some new mutations were identified, such as DNA methyltransferase 3A (DNMT3A), which is associated with the epigenetic regulation and poor treatment outcome of AML. In a large series of 1185 AML patients, we have discovered that Class III mutations which are defined as the ones related with epigenetic regulations, are highly associated with the elder age onset, high WBC count and poor clinical prognosis. It is considered that AML is a disease with multi-step pathogenesis involving the molecular events in different pathways, and the cooperation of the gene mutations affecting transcriptional factors and signal tranduction pathway will lead to the full blown of AML.

关 键 词:急性髓细胞白血病 表观遗传学 基因突变 

分 类 号:R733.71[医药卫生—肿瘤]

 

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