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Over 70% of patients acquire a somatic mutation at specific hotspots (\n                  <jats:italic>R525H\/G530D<\/jats:italic>\n                  ) in the helicase domain of DDX41 in\n                  <jats:italic>trans<\/jats:italic>\n                  , which is linked to disease progression. DDX41 has diverse cellular functions, including RNA splicing, ribosome biogenesis, R-loop resolution and inflammation. However, the mechanisms by which somatic\n                  <jats:italic>DDX41<\/jats:italic>\n                  mutations drive MDS\/AML pathogenesis are yet to be determined. Here, we systematically evaluated the function of pathogenic, missense germline and somatic\n                  <jats:italic>DDX41<\/jats:italic>\n                  mutations. We report that\n                  <jats:italic>DDX41<\/jats:italic>\n                  somatic mutations are gain of function alleles and fail to rescue AML cell growth, distinct from germline\n                  <jats:italic>DDX41<\/jats:italic>\n                  mutations.\n                  <jats:italic>DDX41<\/jats:italic>\n                  somatic mutations R525H and G530D drive widespread splicing changes in isogenic AML cell lines, consistent in genetically engineered murine bone marrow HSPCs and CD34\n                  <jats:sup>+<\/jats:sup>\n                  cells from\n                  <jats:italic>DDX41<\/jats:italic>\n                  -mutant MDS\/AML patients. Mechanistically, DDX41-R525H exhibits increased RNA binding affinity compared to wildtype, with aberrantly spliced RNA targets overlapping with enriched binding. Strikingly, aberrant splicing of SEPTIN7 is enriched exclusively in CD34\n                  <jats:sup>+<\/jats:sup>\n                  HSPCs of patients harboring both germline and somatic\n                  <jats:italic>DDX41<\/jats:italic>\n                  mutations but absent in samples with germline mutation alone or lacking\n                  <jats:italic>DDX41<\/jats:italic>\n                  mutations altogether. SEPTIN7 mis-splicing introduces a premature stop codon resulting in its downregulation at the protein level. SEPTIN7 is a known regulator of cytokinesis, HSC polarity and repopulation capacity. Our results identify a novel mis-spliced candidate, SEPTIN7, whose deregulation implicates a mechanism by which the\n                  <jats:italic>DDX41<\/jats:italic>\n                  somatic mutations promote dysplastic hematopoiesis.\n                <\/jats:p>","DOI":"10.64898\/2026.09.23.753593","type":"posted-content","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:30:19Z","timestamp":1790267419000},"source":"Crossref","is-referenced-by-count":0,"title":["Somatic\n                  <i>DDX41<\/i>\n                  mutations confer neomorphic splicing activity in the pathogenesis of myelodysplastic neoplasms"],"prefix":"10.64898","author":[{"given":"Rasika","family":"Venkataraman","sequence":"first","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"},{"name":"Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noemi","family":"Puccio","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tun-Yun","family":"Hsueh","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Bonner","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fu-Yen","family":"Chang","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica A.","family":"Arriaga-Gomez","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Axia","family":"Song","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takero","family":"Miyagawa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jahan","family":"Rahman","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oluwanifemi","family":"Akinwande","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayantani","family":"Sinha","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ettaib","family":"El Marabti","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"},{"name":"Department of Medicine, Division of Hematology-Oncology, Yale New Haven Hospital, New Haven, CT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert S.","family":"Welner","sequence":"additional","affiliation":[{"name":"Division of Hematology & Oncology and O\u2019Neal Comprehensive Cancer Center at the University of Alabama at Birmingham, Birmingham, AL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Lu","sequence":"additional","affiliation":[{"name":"Division of Hematology & Oncology and O\u2019Neal Comprehensive Cancer Center at the University of Alabama at Birmingham, Birmingham, AL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P. Brent","family":"Ferrell","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Hematology & Oncology and Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5622-3735","authenticated-orcid":false,"given":"Martin","family":"Carroll","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob S.","family":"Appelbaum","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, University of Washington, Seattle, WA, USA"},{"name":"Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4151-3171","authenticated-orcid":false,"given":"Derek L.","family":"Stirewalt","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Abdel-Wahab","sequence":"additional","affiliation":[{"name":"Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7142-6533","authenticated-orcid":false,"given":"Anthony","family":"Rongvaux","sequence":"additional","affiliation":[{"name":"Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA, USA"},{"name":"Department of Immunology, University of Washington School of Medicine, Seattle, WA, 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