DDX41-related myeloid neoplasia
DDX41-related myeloid neoplasia
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DOI：
10.1053/j.seminhematol.2017.04.007
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发表时间：
2017-04-01
影响因子：
3.6
通讯作者：
Mueller-Tidow, Carsten
中科院分区：
文献类型：
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作者：
Maciejewski, Jaroslaw P.;Padgett, Richard A.;Mueller-Tidow, Carsten
虽然家族性白血病综合征的早期表现很典型，但长期的疾病预期可能会掩盖看似自发性疾病的家族特征。 DDX41 基因的种系突变已在几个白血病家族以及大多数看似自发性疾病但具有强烈骨髓瘤家族史的成年患者中发现。与其他家族基因一样，DDX41 突变携带者可以通过获得另一种体细胞突变而形成肿瘤，从而影响两个 DDX41 等位基因。在其他患者中，不同驱动基因的体细胞突变可以在进展过程中替代获得性错义 DDX41。相反，具有杂合体细胞 DDX41 突变的非家族病例表明其他突变可以替代种系创始人 DDX41 病变。在任何一种情况下，DDX41 的完全失活似乎都是细胞致死性的，这解释了为什么移码种系损伤尚未发现伴随着 5q 上 DDX41 位点的缺失。 DDX41 蛋白的精确功能尚不清楚；大量证据表明它参与 RNA 剪接。因此，DDX41 可以包含在目前受骨髓瘤形成影响的一大群突变剪接体基因中。然而，DDX4 似乎是迄今为止白血病中种系剪接体突变的唯一例子。在临床上，DDX41突变病例的识别可能对监测、预后评估以及靶向治疗的设计产生影响。 (C) 2017 Elsevier Inc. 保留所有权利。
While early presentation of familial leukemia syndromes is typical, long disease anticipation may mask cases of familial traits in seemingly spontaneous disease. Germline mutations in DDX41 gene have been discovered in several leukemia families, as well as in mostly adult patients with seemingly spontaneous disease but having strong family histories of myeloid neoplasia. As with other familial genes, DDX41 mutation carriers can develop neoplasia through acquisition of another somatic mutation, thereby affecting both DDX41 alleles. In other patients, somatic mutations of different driver genes can substitute for acquired missense DDX41 during progression. Conversely, non-familial cases with heterozygous somatic DDX41 mutations point towards other mutations that can substitute for the germ line founder DDX41 lesions. In either circumstance, total inactivation of DDX41 appears to be cell-lethal, explaining why frameshift germline lesions have not been found to be accompanied by deletions of the DDX41 locus on 5q. The precise function of the DDX41 protein is unknown; considerable evidence suggests its involvement in RNA splicing. Thus DDX41 can be included in the now large group of mutated spliceosomal genes affected in myeloid neoplasia. However, it appears that DDX4 is so far the only example of a germline spliceosomal mutation in leukemia. Clinically, recognition of DDX41 mutated cases may have implications for surveillance, assessment of prognosis, and, perhaps, for design of targeted therapies. (C) 2017 Elsevier Inc. All rights reserved.