文章：

DNMT3A在血液恶性肿瘤中的作用

DNMT3A in haematological malignancies

原文发布日期：2015-02-19

DOI: 10.1038/nrc3895

类型: Review Article

开放获取: 否

要点：

1. DNA methyltransferase 3A (DNMT3A) belongs to a family of highly conserved DNA methyltransferases that catalyse 5-methylcytosine methylation. Regulatory domains of DNMT3A allow interactions with histone methyltransferases and histones to influence gene expression.
2. DNMT3A is important in embryonic and haematopoietic stem cell (HSC) differentiation, and interacts with DNMT3B to regulate the function of stem cells. Loss of murine Dnmt3a causes unprecedented HSC expansion, clonal dominance, aberrant DNA methylation, an unrepressed stem cell programme and, eventually, haematological malignancies.
3. DNMT3A mutations occur in human HSCs, in which they can act as a pre-leukaemic lesion. Mutant HSC progeny are found in all differentiated lineages in some patients with acute myeloid leukaemia (AML), and mutant HSCs persist during disease remission.
4. DNMT3A mutations occur in diverse haematological malignancies with unique mutational profiles. The R882 hotspot mutation occurs most frequently in AML and has been shown to act as a dominant-negative inhibitor of wild-type DNMT3A enzymatic activity.
5. DNMT3A mutations non-randomly co-occur with a number of other mutations but can also be essentially mutually exclusive of others. This pattern suggests important biological relationships among these genes.
6. The prognostic impact of DNMT3A mutations across various haematological malignancies is inconclusive. A number of studies have found that mutations of DNMT3A confer a poor prognosis, but others have found that DNMT3A status is prognostically neutral.
7. Haematopoiesis becomes clonal in a significant portion of ageing individuals and is associated with increased incidence of haematological malignancy and all-cause mortality; mutations in DNMT3A are highly associated with this phenomenon.
8. Given the strong association between DNMT3A mutations and many types of haematological malignancy and the relatively poor understanding of its mechanistic function, DNMT3A represents an important new target for research and novel therapeutic approaches.

要点翻译：

1. DNA甲基转移酶3A（DNMT3A）属于一个高度保守的DNA甲基转移酶家族，该家族催化5-甲基胞嘧啶甲基化过程。DNMT3A的调控结构域能够与组蛋白甲基转移酶及组蛋白相互作用，从而调控基因表达。
2. DNMT3A在胚胎和造血干细胞（HSC）分化过程中具有重要作用，并与DNMT3B协同调控干细胞功能。小鼠模型中Dnmt3a的缺失会导致造血干细胞异常扩增、克隆优势、DNA甲基化紊乱、干细胞程序失控，最终引发血液系统恶性肿瘤。
3. 人类造血干细胞中存在的DNMT3A突变可作为白血病前病变。在某些急性髓系白血病（AML）患者的所有分化谱系中均可发现突变型HSC后代，且突变型HSC在疾病缓解期仍持续存在。
4. DNMT3A突变广泛存在于具有独特突变谱的各类血液系统恶性肿瘤中。R882热点突变在AML中最常见，已被证实对野生型DNMT3A酶活性具有显性负抑制作用。
5. DNMT3A突变与多种其他突变存在非随机共现现象，但也可与某些突变基本互斥。这种模式揭示了这些基因间重要的生物学关联。
6. DNMT3A突变对不同血液系统恶性肿瘤的预后影响尚无定论。多项研究发现DNMT3A突变提示预后不良，但也有研究显示其预后价值呈中性。
7. 相当比例老年个体的造血过程呈现克隆性，这与血液恶性肿瘤发生率和全因死亡率升高相关；DNMT3A突变与此现象高度相关。
8. 鉴于DNMT3A突变与多种血液系统恶性肿瘤的密切关联，以及对其机制功能认识的相对不足，DNMT3A已成为重要的新型研究靶点和创新治疗方向。

英文摘要：

DNA methylation patterns are disrupted in various malignancies, suggesting a role in the development of cancer, but genetic aberrations directly linking the DNA methylation machinery to malignancies were rarely observed, so this association remained largely correlative. Recently, however, mutations in the gene encoding DNA methyltransferase 3A (DNMT3A) were reported in patients with acute myeloid leukaemia (AML), and subsequently in patients with various other haematological malignancies, pointing to DNMT3A as a critically important new tumour suppressor. Here, we review the clinical findings related to DNMT3A, tie these data to insights from basic science studies conducted over the past 20 years and present a roadmap for future research that should advance the agenda for new therapeutic strategies.

摘要翻译： 

DNA甲基化模式在多种恶性肿瘤中受到干扰，提示其在癌症发生中的作用，但直接将DNA甲基化机制与恶性肿瘤关联的基因异常却很少被观察到，因此这种关联主要停留在相关性层面。然而，最近在急性髓系白血病（AML）患者中发现了编码DNA甲基转移酶3A（DNMT3A）的基因突变，随后在其他多种血液系统恶性肿瘤患者中也发现了该突变，表明DNMT3A是一个极为重要的新型肿瘤抑制因子。本文综述了与DNMT3A相关的临床发现，将这些数据与过去20年基础科学研究的见解联系起来，并提出了未来研究的路线图，以推动新治疗策略的发展。

原文链接：

DNMT3A in haematological malignancies