LAUSR

Simple Summary The DEAD-box RNA helicase 41, DDX41, is one of the most frequently identified mutations in myeloid neoplasms with germline predispositions, which represents 2% of the entire MDS/AML population. DDX41 is located at 5q35.3, and its mutation has unique features of male predominance and long-term cytopenia before the development of myeloid neoplasms. So far, mechanism studies revealed that DDX41 mutations, affected by both germline and somatic mutations, can be pathogenic by impairments in the normal function of genes involving RNA splicing and processing, ribosomal biogenesis, metabolism, cycle progression, and innate immunity. We are gaining a better understanding of disease from more studies coming out with larger cohorts. The survival impact of the mutation remains unclear, although recent larger studies suggest a better treatment response and survival in higher risk MDS/AML. Several studies showed a good response to lenalidomide in certain patients with MDS with DDX41 mutations. Early identification of stem-cell transplant donors in the family for patients with DDX41 mutations is crucial to avoid donor-derived leukemia from germline carriers. In this article, we reviewed the current understanding of DDX41 mutations in AML/MDS, including its pathogenesis and clinical characteristics, outcome, and treatment. Abstract The DEAD-box RNA helicase 41 gene, DDX41, is frequently mutated in hereditary myeloid neoplasms, identified in 2% of entire patients with AML/MDS. The pathogenesis of DDX41 mutation is related to the defect in the gene’s normal functions of RNA and innate immunity. About 80% of patients with germline DDX41 mutations have somatic mutations in another allele, resulting in the biallelic DDX41 mutation. Patients with the disease with DDX41 mutations reportedly often present with the higher-grade disease, but there are conflicting reports about its impact on survival outcomes. Recent studies using larger cohorts reported a favorable outcome with a better response to standard therapies in patients with DDX41 mutations to patients without DDX41 mutations. For stem-cell transplantation, it is important for patients with DDX41 germline mutations to identify family donors early to improve outcomes. Still, there is a gap in knowledge on whether germline DDX41 mutations and its pathology features can be targetable for treatment, and what constitutes an appropriate screening/surveillance strategy for identified carriers. This article reviews our current understanding of DDX41 mutations in myeloid neoplasms in pathologic and clinical features and their clinical implications.