文章：

骨髓增生异常综合征的遗传学：从克隆造血到继发性白血病

The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia

原文发布日期：2016-11-11

DOI: 10.1038/nrc.2016.112

类型: Review Article

开放获取: 否

要点：

1. Myelodysplastic syndrome (MDS) is one of the most common haematological malignancies and is associated with increased age and exposure to previous chemotherapy and radiation. It is characterized by cytopenias, morphological dysplasia and a propensity to transform to acute myeloid leukaemia (AML).
2. Clonal haematopoiesis of indeterminate potential (CHIP) is a condition in which a substantial percentage of haematopoietic cells bear a somatic mutation in a gene that is recurrently mutated in haematological malignancies, including MDS. CHIP is strongly associated with age and an increased risk of haematological malignancy.
3. More than 50 recurrently mutated genes have been identified in MDS, many of which occur in genes encoding RNA splicing factors, epigenetic regulators, haematopoietic transcription factors and kinase signalling pathways.
4. Individual mutations in MDS are associated with specific morphological findings, have independent prognostic significance and can predict response to therapy in some cases.
5. AML that arises out of a pre-existing MDS can be distinguished from de novo AML by the presence of specific mutations, such as those in splicing factors and certain epigenetic regulators.
6. Some mutations are associated with increased sensitivity or resistance to standard therapeutic interventions, providing new targets for the development of novel therapeutic agents.
7. Currently, allogeneic haematopoietic stem cell transplantation is the only known curative treatment for MDS.

要点翻译：

1. 骨髓增生异常综合征（MDS）是最常见的血液恶性肿瘤之一，其发生与年龄增长及既往化疗和放射治疗暴露相关。该疾病以血细胞减少、形态学发育异常及易转化为急性髓系白血病（AML）为特征。
2. 意义未明的克隆性造血（CHIP）是指相当比例的造血细胞携带血液恶性肿瘤（包括MDS）中反复突变的基因发生体细胞突变的状态。CHIP与年龄增长密切相关，并会显著增加血液恶性肿瘤的发病风险。
3. 目前在MDS中已发现50多个反复突变的基因，其中许多涉及RNA剪接因子、表观遗传调控因子、造血转录因子及激酶信号通路相关基因的编码。
4. MDS中的特定基因突变与特征性形态学表现相关，具有独立的预后判断价值，在某些情况下还能预测治疗反应。
5. 由既存MDS进展而来的AML可通过特定突变与原发性AML相区分，例如剪接因子和某些表观遗传调控因子的突变。
6. 某些基因突变与标准治疗干预的敏感性增强或耐药性相关，这为开发新型治疗药物提供了新靶点。
7. 目前，异基因造血干细胞移植是MDS唯一已知可治愈的治疗方法。

英文摘要：

Myelodysplastic syndrome (MDS) is a clonal disease that arises from the expansion of mutated haematopoietic stem cells. In a spectrum of myeloid disorders ranging from clonal haematopoiesis of indeterminate potential (CHIP) to secondary acute myeloid leukaemia (sAML), MDS is distinguished by the presence of peripheral blood cytopenias, dysplastic haematopoietic differentiation and the absence of features that define acute leukaemia. More than 50 recurrently mutated genes are involved in the pathogenesis of MDS, including genes that encode proteins involved in pre-mRNA splicing, epigenetic regulation and transcription. In this Review we discuss the molecular processes that lead to CHIP and further clonal evolution to MDS and sAML. We also highlight the ways in which these insights are shaping the clinical management of MDS, including classification schemata, prognostic scoring systems and therapeutic approaches.

摘要翻译： 

骨髓增生异常综合征（MDS）是一种克隆性疾病，由突变的造血干细胞扩增引起。在从意义未明的克隆性造血（CHIP）到继发性急性髓系白血病（sAML）的一系列髓系疾病中，MDS 的特点在于存在外周血细胞减少、造血分化异常，且缺乏定义急性白血病的特征。MDS 的发病涉及 50 多个反复突变的基因，包括编码参与前体 mRNA 剪接、表观遗传调控和转录的蛋白质的基因。在本综述中，我们讨论了导致 CHIP 以及进一步克隆演化为 MDS 和 sAML 的分子过程。我们还强调了这些认识如何影响 MDS 的临床管理，包括分类方案、预后评分系统和治疗方法。

原文链接：

The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia