{
  "id": 9580597,
  "title": "Somatic DDX41 mutations confer neomorphic splicing activity in the pathogenesis of myelodysplastic neoplasms",
  "url": "https://urgent.news/2026/09/24/somatic-ddx41-mutations-confer-neomorphic-splicing-activity-in-the",
  "topic": "science",
  "section": "Science",
  "published": "2026-09-24T00:00:00.000Z",
  "source": {
    "name": "bioRxiv",
    "slug": "biorxiv",
    "url": "https://www.biorxiv.org/content/10.64898/2026.09.23.753593v1?rss=1"
  },
  "original_language": "en",
  "account": "Somatic DDX41 mutations play a significant role in the development of myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML), accounting for 5-7% of AML cases. In approximately 70% of affected patients, a somatic mutation occurs at specific hotspots (R525H/G530D) within the helicase domain of the DDX41 helicase. This mutation is associated with the progression of the disease. DDX41 is involved in various cellular processes, such as RNA splicing, ribosome biogenesis, R-loop resolution, and inflammation. However, the exact mechanisms through which somatic DDX41 mutations contribute to MDS/AML pathogenesis remain unclear. In this study, researchers systematically assessed the function of pathogenic, missense germline, and somatic DDX41 mutations. They discovered that somatic DDX41 mutations act as gain-of-function alleles, resulting in the inability to restore AML cell growth, which is different from the behavior of germline DDX41 mutations. Specifically, the R525H and G530D mutations drive extensive changes in splicing patterns within isogenic AML cell lines, both in engineered murine bone marrow hematopoietic stem and progenitor cells (HSPCs) and CD34+ cells derived from DDX41-mutant MDS/AML patients. The R525H mutation demonstrates increased RNA binding affinity when compared to the wild-type DDX41. The aberrantly spliced RNA targets of the R525H mutation overlap with those that are enriched in the binding sites. Notably, the mis-splicing of SEPTIN7 is exclusive to CD34+ HSPCs from patients who have both germline and somatic DDX41 mutations, but not in samples with germline mutations alone or without DDX41 mutations. The mis-splicing of SEPTIN7 introduces a premature stop codon, leading to a reduction in its protein levels. SEPTIN7 is known to regulate cytokinesis, hematopoietic stem cell (HSC) polarity, and HSC repopulation capacity. The findings suggest that SEPTIN7 mis-splicing is a novel candidate whose deregulation implies a mechanism by which somatic DDX41 mutations contribute to dysplastic hematopoiesis.",
  "summary": "Germline mutations in the RNA helicase DDX41 are the most common genetic predisposition to myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), representing 5-7% of AML. Over 70% of patients acquire a somatic mutation at specific hotspots (R525H/G530D) in the helicase domain of DDX41 in trans, which is linked to disease progression. DDX41 has diverse cellular functions, including RNA…",
  "key_points": [],
  "editors_take": null,
  "illustration": null,
  "coverage": {
    "outlets": 1,
    "also_reported_by": []
  },
  "ai_generated": true,
  "disclaimer": "Summaries, key points and the editor’s take are written by software from other outlets’ reporting and may contain errors — always check the linked original."
}