Maciejewski Jaroslaw P, Padgett Richard A, Brown Anna L, Müller-Tidow Carsten
Translational Hematology and Oncology Department, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA.
Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Semin Hematol. 2017 Apr;54(2):94-97. doi: 10.1053/j.seminhematol.2017.04.007. Epub 2017 Apr 21.
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.
虽然家族性白血病综合征通常早期发病，但疾病的长期预期可能会掩盖看似散发性疾病中的家族性特征病例。在几个白血病家族以及大多是患有看似散发性疾病但有髓系肿瘤家族史的成年患者中，已发现DDX41基因的种系突变。与其他家族性基因一样，DDX41突变携带者可通过获得另一个体细胞突变而发生肿瘤，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在疾病进展过程中替代获得性错义DDX41。相反，具有杂合体细胞DDX41突变的非家族性病例指向可替代种系奠基性DDX41病变的其他突变。在任何一种情况下，DDX41的完全失活似乎对细胞是致死性的，这就解释了为什么未发现移码种系病变伴有5q上DDX41基因座的缺失。DDX41蛋白的确切功能尚不清楚；大量证据表明其参与RNA剪接。因此，DDX41可被纳入目前在髓系肿瘤中受影响的大量突变剪接体基因中。然而，DDX41似乎是迄今为止白血病中种系剪接体突变的唯一例子。临床上，识别DDX41突变病例可能对监测、预后评估以及或许对靶向治疗的设计有影响。
