Sensitivity to ATR-CHK1 pathway inhibition in AML/MDS is enhanced by <i>SRSF2</i> mutations and reduced by RUNX1 loss.

ABSTRACT: SRSF2 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 SRSF2 mutations. Ex vivo drug-sensitivity testing of bone marrow cells from AML patients and healthy donors showed that SRSF2-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 SRSF2 ^P95H/L/R mutations. RNA sequencing confirmed splicing aberrations characteristic of MDS/AML in these clones. We found that SRSF2 ^P95H/L/R sensitize leukemia cel

SUBMITTER: Eldfors S 

PROVIDER: S-EPMC12632562 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature