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

Purpose of Review While DDX41 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 on DDX41m, roles of DDX41 in oncogenesis, mechanisms of clonal evolution with somatic DDX41m, and clinical phenotypes and management of MDS/AML in patients harboring DDX41m. Recent Findings DDX41 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 bearing DDX41m suggests that defects in DDX41 lead to loss of a tumor suppressor function, likely related to activities in RNA splicing and processing pathways. Seventy percent of cancer cases with DDX41m 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 somatic DDX41m of the second allele is acquired in 70% of cases, leading to hematological malignancy. Myeloid neoplasms with DDX41m 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. Summary Distinct clinical/pathologic features and favorable outcomes in MDS/AML highlight the need for standardized classification and gene specific guidelines that could assist in management decisions in patients with DDX41m.

Automated summary

DDX41 mutation is one of the most prevalent predisposition genes in adult myelodysplastic syndrome/acute myeloid leukemia. Most patients with DDX41 mutation do not have a family history of MDS/AML. DDX41 mutation leads to defects in cell growth and viability, likely related to the loss of tumor suppressor function. 70% of DDX41 mutations are associated with MDS/AML, with 25% of mutations being inherited mutations from germline cells. Recent studies suggest that a subgroup of patients with DDX41 mutation in myeloid neoplasms have a better clinical course and long-term survival.