Myeloid neoplasms with germline DDX41 mutation
Myeloid neoplasms with germline DDX41 mutation
复制标题
DOI：
10.1007/s12185-017-2260-y
复制
发表时间：
2017-08-01
影响因子：
2.1
通讯作者：
Brown, Anna L.
中科院分区：
文献类型：
--
作者：
Cheah, Jesse J. C.;Hahn, Christopher N.;Brown, Anna L.
最近，DDX 41突变已被确定为生殖细胞和获得性体细胞突变的家庭与多个案件的迟发性骨髓增生异常综合征（MDS）和/或急性髓性白血病。大多数生殖系突变是移码突变，表明DDX 41作为肿瘤抑制因子的功能丧失，并且在大多数生殖系突变肿瘤中发现了常见的体细胞错义突变。临床上，DDX 41突变导致在与散发性队列中观察到的年龄相似的年龄发生高危MDS，这对血液学家识别家族背景提出了独特的挑战。在功能上，DDX 41已被证明有助于多种途径和过程，包括mRNA剪接，先天免疫和rRNA加工。DDX 41的突变导致这些基因中的每一种的畸变，可能会影响肿瘤发生-启动、维持或进展。这篇综述讨论了由于DDX 41突变导致的骨髓恶性肿瘤易感性的各种分子、临床和生物学方面，并强调了这些方面如何通过使用途径特异性抑制剂来提示潜在的治疗机会。
Recently, DDX41 mutations have been identified both as germline and acquired somatic mutations in families with multiple cases of late-onset myelodysplastic syndrome (MDS) and/or acute myeloid leukemia. The majority of germline mutations are frameshift mutations suggesting loss of function with DDX41 acting as a tumor suppressor, and there is a common somatic missense mutation found in a majority of germline mutated tumors. Clinically, DDX41 mutations lead to development of high-risk MDS at an age similar to that observed in sporadic cohorts, presenting a unique challenge to hematologists in recognizing the familial context. Functionally, DDX41 has been shown to contribute to multiple pathways and processes including mRNA splicing, innate immunity and rRNA processing. Mutations in DDX41 result in aberrations to each of these in ways that could potentially impact on tumorigenesis-initiation, maintenance or progression. This review discusses the various molecular, clinical and biological aspects of myeloid malignancy predisposition due to DDX41 mutation and highlights how each of these suggest potential therapeutic opportunities through the use of pathway-specific inhibitors.