Germline and Somatic Defects in DDX41 and its Impact on Myeloid Neoplasms

AbstractPurpose of ReviewWhileDDX41 mutation (m) is one of the most prevalent predisposition genes in adult myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), most patients do not always present with a family history of MDS/AML. In this review, we will be highlighting epidemiological data onDDX41m, roles ofDDX41 in oncogenesis, mechanisms of clonal evolution with somaticDDX41m, and clinical phenotypes and management of MDS/AML in patients harboringDDX41m.Recent FindingsDDX41 encodes a DEAD-box helicase protein that is considered essential for cell growth and viability. High incidence of myeloid malignancies and other cancers in patients bearingDDX41m suggests that defects inDDX41 lead to loss of a tumor suppressor function, likely related to activities in RNA splicing and processing pathways. Seventy percent of cancer cases withDDX41m are associated with MDS/AML alone. More than 65% of familial cases harbor heterozygous germline frameshift mutations, of which p.D140Gfs*2 is the most common. A somaticDDX41m of the second allele is acquired in 70% of cases, leading to hematological malignancy. Myeloid neoplasms withDDX41m are typically characterized by long latency, high-risk disease at presentation with normal cytogenetics and without any additional molecular markers. Recent reports suggests that a subgroup of these patients have an indolent clinical course and have a better long-term survival compared to favorable or intermediate risk AML.SummaryDistinct clinical/pa...
Source: Current Hematologic Malignancy Reports - Category: Hematology Source Type: research