Germline DDX41 variants in myeloid neoplasms (MNs) are not uncommon, and we explored the prevalence and characterized the clinical and pathologic features in a cohort of 3132 unrelated adult MN patients. By targeted next-generation sequencing, we identified 28 patients (20 men and 8 women) with pathogenic germline DDX41 variants who developed acute myeloid leukemia (AML), in which only 3 (11%) had a family history (FH) of MNs. A subacute clinical course of cytopenia (mean duration of 11.2 months, range 0-72 months) prior to the initial AML diagnosis was accompanied by a low blast count (median at 30%, range 20-70%) in hypocellular marrows (93% of all patients), in vast contrast to the typical proliferative subtypes of AML in the elderly. Most patients had a normal karyotype (75%) and acquired a second DDX41 variant (69%). A favorable overall survival (OS) was observed in comparison to that of common subtypes of AML with wild-type DDX41 in age-matched patients. Our study demonstrated that the frequent germline pathogenic DDX41 variants characterized a clinically distinct AML entity. Features characteristic of DDX41-mutated AML include male predominance, often lack of FH, indolent course, low proliferative potential, frequent somatic DDX41 variants, and a favorable OS.
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Germline DDX41 mutations in myeloid neoplasms: the current clinical and molecular understanding.
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Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center.
Purpose Of Review: DDX41 mutations are the most common cause of germline predisposition to adult-onset myeloid neoplasms. The unique mutational landscape and clinical features indicate a distinct molecular pathogenesis, but the precise mechanism by which DDX41 mutations cause disease is poorly understood, owing to the multitude of DDX41 functions. In this review, we will update DDX41's known functions, present unique clinical features and treatment considerations, and summarize the current understanding of the molecular pathogenesis of the disease.
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Deleterious germline variants constitute the most common inherited predisposition disorder linked to myeloid neoplasms (MNs). The role of DDX41 in hematopoiesis and how its germline and somatic mutations contribute to MNs remain unclear. Here we show that DDX41 is essential for erythropoiesis but dispensable for the development of other hematopoietic lineages.
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Epidemiological evidence of familial predispositions to myeloid malignancies and myeloproliferative neoplasms (MPN) has long been recognised, but recent studies have added to knowledge of specific germline variants in multiple genes that contribute to the familial risk. These variants may be common risk alleles in the general population but have low penetrance and cause sporadic MPN, such as the JAK2 46/1 haplotype, the variant most strongly associated with MPN. Association studies are increasingly identifying other MPN susceptibility genes such as TERT, MECOM, and SH2B3, while some common variants in DDX41 and RUNX1 appear to lead to a spectrum of myeloid malignancies.
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