{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:41:52Z","timestamp":1785426112888,"version":"3.56.0"},"posted":{"date-parts":[[2025,10,7]]},"group-title":"Cancer Biology","reference-count":52,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T00:00:00Z","timestamp":1759795200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002341","name":"Research Council of Finland","doi-asserted-by":"crossref","award":["334273"],"award-info":[{"award-number":["334273"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/00ckakm23","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004155","name":"Magnus Ehrnrooth Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004155","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/031p7wh32","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/04m0xav37","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P50CA171963"],"award-info":[{"award-number":["P50CA171963"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/03h22gm35","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Lottie C. Hardy Charitable Trust"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  <jats:italic>SRSF2<\/jats:italic>\n                  mutations occur in up to 25% of acute myeloid leukemia (AML) and 17% of myelodysplastic syndrome (MDS) cases and are associated with poor prognosis, yet no mutation-directed therapy exists.\n                <\/jats:p>\n                <jats:p>\n                  Here, we aimed to identify therapeutically targetable vulnerabilities in MDS\/AML with\n                  <jats:italic>SRSF2<\/jats:italic>\n                  mutations. Ex vivo drug-sensitivity testing of bone marrow cells from AML patients and healthy donors showed that\n                  <jats:italic>SRSF2<\/jats:italic>\n                  -mutant cells are sensitive to inhibitors of CHK1, and WEE1 DNA damage response (DDR) kinases.\n                <\/jats:p>\n                <jats:p>\n                  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                  sensitize leukemia cells to ATR\u2013CHK1\u2013WEE1 inhibition. Bone marrow progenitors from\n                  <jats:italic>Srsf2<\/jats:italic>\n                  <jats:sup>P95H<\/jats:sup>\n                  and\n                  <jats:italic>U2AF1<\/jats:italic>\n                  <jats:sup>S34F<\/jats:sup>\n                  knock-in mice showed heightened sensitivity to CHK1 inhibition, corroborating the human data.\n                <\/jats:p>\n                <jats:p>\n                  In contrast,\n                  <jats:italic>RUNX1<\/jats:italic>\n                  mutations were linked to resistance against CHK1 and WEE1 inhibition in\n                  <jats:italic>SRSF2<\/jats:italic>\n                  -mutant AML samples.\n                  <jats:italic>Runx1<\/jats:italic>\n                  loss 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 is a mechanism of resistance.\n                <\/jats:p>\n                <jats:p>\n                  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. These biomarkers can support patient stratification in MDS\/AML.\n                <\/jats:p>","DOI":"10.1101\/2025.10.06.680457","type":"posted-content","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T14:20:20Z","timestamp":1759846820000},"source":"Crossref","is-referenced-by-count":0,"title":["Sensitivity to ATR\u2013CHK1 pathway inhibition in AML\/MDS is enhanced by\n                  <i>SRSF2<\/i>\n                  mutations and reduced by RUNX1 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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\/0000-0003-4112-5902","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","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7710-1171","authenticated-orcid":false,"given":"Timothy 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