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To test causality, we engineered isogenic K562 cell line clones expressing\n                    <jats:italic>SRSF2<\/jats:italic>\n                    <jats:sup>P95H\/L\/R<\/jats:sup>\n                    mutations. RNA sequencing confirmed splicing aberrations characteristic of MDS\/AML in these clones. We found that\n                    <jats:italic>SRSF2<\/jats:italic>\n                    <jats:sup>P95H\/L\/R<\/jats:sup>\n                    sensitizes cells to ATR\u2013CHK1\u2013WEE1 inhibition. Bone marrow progenitors from\n                    <jats:italic>Srsf2<\/jats:italic>\n                    <jats:sup>P95H<\/jats:sup>\n                    knock-in mice showed heightened sensitivity to CHK1 inhibition, corroborating the human\n                    <jats:italic>SRSF2<\/jats:italic>\n                    -mutant data.\n                    <jats:italic>U2af1<\/jats:italic>\n                    <jats:sup>S34F<\/jats:sup>\n                    knock-in mouse progenitors extended this vulnerability to another spliceosome-mutant context. In contrast,\n                    <jats:italic>RUNX1<\/jats:italic>\n                    mutations were linked to resistance to CHK1 and WEE1 inhibition in\n                    <jats:italic>SRSF2<\/jats:italic>\n                    -mutant AML samples.\n                    <jats:italic>Runx1<\/jats:italic>\n                    disruption also caused resistance to CHK1 inhibitors in knock-in mouse progenitors harboring\n                    <jats:italic>Srsf2<\/jats:italic>\n                    <jats:sup>P95H<\/jats:sup>\n                    or\n                    <jats:italic>U2af1<\/jats:italic>\n                    <jats:sup>S34F<\/jats:sup>\n                    , indicating that\n                    <jats:italic>RUNX1<\/jats:italic>\n                    loss of function is a mechanism of resistance. In conclusion,\n                    <jats:italic>SRSF2<\/jats:italic>\n                    and\n                    <jats:italic>U2AF1<\/jats:italic>\n                    mutations are biomarkers of sensitivity to ATR\u2013CHK1 pathway inhibitors, while\n                    <jats:italic>RUNX1<\/jats:italic>\n                    mutations cause resistance in splicing factor-mutant cells. These biomarkers can support patient stratification in MDS\/AML.\n                  <\/jats:p>","DOI":"10.1038\/s41375-026-03142-7","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:11:59Z","timestamp":1791288719000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sensitivity to ATR\u2013CHK1 pathway inhibition in MDS\/AML is enhanced by SRSF2 mutations and reduced by RUNX1 loss"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5056-4750","authenticated-orcid":false,"given":"Samuli","family":"Eldfors","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumit","family":"Rai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vineet","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tareq","family":"Hossan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia Cabrera","family":"Pastrana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Bertino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelique","family":"Gilbert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6293-4632","authenticated-orcid":false,"given":"Sridhar Nonavinkere","family":"Srivatsan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4112-5902","authenticated-orcid":false,"given":"Kimmo","family":"Porkka","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"}]},{"given":"Timothy A.","family":"Graubert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,6]]},"reference":[{"key":"3142_CR1","doi-asserted-by":"publisher","first-page":"2209","DOI":"10.1056\/NEJMoa1516192","volume":"374","author":"E Papaemmanuil","year":"2016","unstructured":"Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. 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TAG has received research funding from AstraZeneca. The remaining authors declare no competing interests.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"All methods were performed in accordance with the relevant guidelines and regulations. The collection and use of human bone marrow samples were approved by the Helsinki University Hospital Ethics Committee under permit numbers 239\/13\/03\/00\/2010 and 303\/13\/03\/01\/2011 and were conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all participants. All experiments involving live vertebrate animals were approved by the Washington University Institutional Animal Care and Use Committee under protocol number 23-0434 and were performed in accordance with the relevant institutional guidelines and regulations and the National Institutes of Health guidelines for the care and use of laboratory animals.","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}}]}}