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Hirsch Foundation Break Through Cancer"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Leukemia"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Recurrent somatic mutations in the spliceosome genes\n                    <jats:italic>SF3B1<\/jats:italic>\n                    ,\n                    <jats:italic>SRSF2<\/jats:italic>\n                    , and\n                    <jats:italic>U2AF1<\/jats:italic>\n                    are frequently identified in patients with myeloid neoplasms, such as myelodysplastic syndromes. We characterized the in vivo consequences of expressing two hotspot mutations in\n                    <jats:italic>U2AF1<\/jats:italic>\n                    that code for the S34F and Q157R substitutions. Our results indicate that the two mutations induce distinct hematopoietic phenotypes in mice, suggesting that the\n                    <jats:italic>U2AF1<\/jats:italic>\n                    <jats:sup>S34F<\/jats:sup>\n                    and\n                    <jats:italic>U2AF1<\/jats:italic>\n                    <jats:sup>Q157R<\/jats:sup>\n                    mutations should not be conflated as they may impact disease pathogenesis differently in patients. Mice expressing\n                    <jats:italic>U2af1<\/jats:italic>\n                    <jats:sup>S34F<\/jats:sup>\n                    have a more severe reduction in their blood and bone marrow cell counts and reduced stem cell repopulating ability, compared to mice expressing\n                    <jats:italic>U2af1<\/jats:italic>\n                    <jats:sup>Q157R<\/jats:sup>\n                    . The expression and splicing of target genes are largely unique between the mutations, in both mouse and human samples, potentially driving the phenotypic differences induced by either mutation. The two mutations co-occur with different gene mutations in patients and are not equally represented across myeloid neoplasms, suggesting that multiple mechanisms likely drive U2AF1-mutant disease pathogenesis. Collectively, our results support that\n                    <jats:italic>U2AF1<\/jats:italic>\n                    <jats:sup>S34F<\/jats:sup>\n                    and\n                    <jats:italic>U2AF1<\/jats:italic>\n                    <jats:sup>Q157R<\/jats:sup>\n                    mutations induce distinct hematopoietic, gene expression, and RNA splicing phenotypes in vivo. Larger population studies will be needed to determine if these phenotypic changes translate into clinico-pathologic differences in patients, warranting separate classification.\n                  <\/jats:p>","DOI":"10.1038\/s41375-026-02974-7","type":"journal-article","created":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T11:52:31Z","timestamp":1778068351000},"page":"1467-1481","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["U2af1S34F and U2af1Q157R myeloid neoplasm-associated hotspot mutations induce distinct hematopoietic phenotypes in mice"],"prefix":"10.1038","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4269-4701","authenticated-orcid":false,"given":"Michael O.","family":"Alberti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6293-4632","authenticated-orcid":false,"given":"Sridhar","family":"Nonavinkere Srivatsan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis L.","family":"Fei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7969-3983","authenticated-orcid":false,"given":"Mengou","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9748-2020","authenticated-orcid":false,"given":"Claudia Cabrera","family":"Pastrana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique","family":"Chavez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7970-702X","authenticated-orcid":false,"given":"Stefan P.","family":"Tarnawsky","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Grieb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7710-1171","authenticated-orcid":false,"given":"Timothy A.","family":"Graubert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omar","family":"Abdel-Wahab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7753-1091","authenticated-orcid":false,"given":"Matthew J.","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,6]]},"reference":[{"key":"2974_CR1","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1038\/nature10496","volume":"478","author":"K Yoshida","year":"2011","unstructured":"Yoshida K, Sanada M, Shiraishi Y, Nowak D, Nagata Y, Yamamoto R, et al. 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