Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; and.
Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden.
Blood. 2019 Mar 7;133(10):1049-1059. doi: 10.1182/blood-2018-10-844621. Epub 2019 Jan 22.
Our knowledge about the genetics of myelodysplastic syndromes (MDS) and related myeloid disorders has been dramatically improved during the past decade, in which revolutionized sequencing technologies have played a major role. Through intensive efforts of sequencing of a large number of MDS genomes, a comprehensive registry of driver mutations recurrently found in a recognizable fraction of MDS patients has been revealed, and ongoing efforts are being made to clarify their impacts on clinical phenotype and prognosis, as well as their role in the pathogenesis of MDS. Among major mutational targets in MDS are the molecules involved in DNA methylations, chromatin modification, RNA splicing, transcription, signal transduction, cohesin regulation, and DNA repair. Showing substantial overlaps with driver mutations seen in acute myeloid leukemia (AML), as well as age-related clonal hematopoiesis in healthy individuals, these mutations are presumed to have a common clonal origin. Mutations are thought to be acquired and positively selected in a well-organized manner to allow for expansion of the initiating clone to compromise normal hematopoiesis, ultimately giving rise to MDS and subsequent transformation to AML in many patients. Significant correlations between mutations suggest the presence of functional interactions between mutations, which dictate disease progression. Mutations are frequently associated with specific disease phenotype, drug response, and clinical outcomes, and thus, it is essential to be familiar with MDS genetics for better management of patients. This review aims to provide a brief overview of the recent progresses in MDS genetics.
在过去的十年中，我们对骨髓增生异常综合征（MDS）和相关髓系疾病的遗传学知识有了显著的提高，其中革命性的测序技术发挥了重要作用。通过对大量 MDS 基因组进行测序的努力，揭示了在可识别的 MDS 患者中经常发现的驱动突变的综合目录，并且正在努力阐明它们对临床表型和预后的影响，以及它们在 MDS 发病机制中的作用。MDS 的主要突变靶点包括涉及 DNA 甲基化、染色质修饰、RNA 剪接、转录、信号转导、黏合调控和 DNA 修复的分子。这些突变与急性髓系白血病（AML）中的驱动突变以及健康个体中与年龄相关的克隆性造血有很大的重叠，据推测它们具有共同的克隆起源。突变被认为是以一种有序的方式获得和积极选择的，以允许起始克隆的扩展，从而损害正常造血，最终导致 MDS，并在许多患者中随后转化为 AML。突变之间存在显著相关性，提示突变之间存在功能相互作用，这决定了疾病的进展。突变通常与特定的疾病表型、药物反应和临床结果相关，因此，熟悉 MDS 遗传学对于更好地管理患者至关重要。本文旨在简要概述 MDS 遗传学的最新进展。
