biostudies-literatureUnknownEldfors SNCI NIH HHS<i>SRSF2</i> 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. Here, we aimed to identify therapeutically targetable vulnerabilities in MDS/AML with <i>SRSF2</i> mutations. Ex vivo drug-sensitivity testing of bone marrow cells from AML patients and healthy donors showed that <i>SRSF2</i>-mutant cells are sensitive to inhibitors of CHK1, and WEE1 DNA damage response (DDR) kinases. To test causality, we engineered isogenic K562 cell line clones expressing <i>SRSF2</i> ^P95H/L/R mutations. RNA sequencing confirmed splicing aberrations characteristic of MDS/AML in these clones. We found that <i>SRSF2</i> ^P95H/L/R sensitize leukemia celbioRxiv : the preprint server for biology2025.10.06.680457https://www.ebi.ac.uk/biostudies/studies/S-EPMC12632562biostudies-literatureSensitivity to ATR-CHK1 pathway inhibition in AML/MDS is enhanced by &lt;i&gt;SRSF2&lt;/i&gt; mutations and reduced by RUNX1 loss.PMC12632562P50 CA171963Pastrana CCGilbert AGraubert TASharma VBertino APorkka KEldfors SRai SWalter MHossan TfalseSensitivity to ATR-CHK1 pathway inhibition in AML/MDS is enhanced by &lt;i&gt;SRSF2&lt;/i&gt; mutations and reduced by RUNX1 loss.<i>SRSF2</i> 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. Here, we aimed to identify therapeutically targetable vulnerabilities in MDS/AML with <i>SRSF2</i> mutations. Ex vivo drug-sensitivity testing of bone marrow cells from AML patients and healthy donors showed that <i>SRSF2</i>-mutant cells are sensitive to inhibitors of CHK1, and WEE1 DNA damage response (DDR) kinases. To test causality, we engineered isogenic K562 cell line clones expressing <i>SRSF2</i> ^P95H/L/R mutations. RNA sequencing confirmed splicing aberrations characteristic of MDS/AML in these clones. We found that <i>SRSF2</i> ^P95H/L/R sensitize leukemia cel2025-01-01T00:00:00Z2025 Oct2026-06-10T03:10:37.017Z2026-06-10T03:07:20.65ZS-EPMC126325624127960610.1101/2025.10.06.680457