Sensitivity to ATR–CHK1 pathway inhibition in AML/MDS is enhanced by SRSF2 mutations and reduced by RUNX1 loss Article Swipe
Samuli Eldfors
,
Sumit Rai
,
V. D. Sharma
,
Tareq Hossan
,
Claudia Cabrera Pastrana
,
Amy M. Bertino
,
Angelique Gilbert
,
Kimmo Porkka
,
Matthew J. Walter
,
Timothy A. Graubert
·
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.10.06.680457
YOU?
·
· 2025
· Open Access
·
· DOI: https://doi.org/10.1101/2025.10.06.680457
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 cells to ATR–CHK1–WEE1 inhibition. Bone marrow progenitors from Srsf2 P95H and U2AF1 S34F knock-in mice showed heightened sensitivity to CHK1 inhibition, corroborating the human data. In contrast, RUNX1 mutations were linked to resistance against CHK1 and WEE1 inhibition in SRSF2 -mutant AML samples. Runx1 loss also caused resistance to CHK1 inhibitors in knock-in mouse progenitors harboring Srsf2 P95H or U2AF1 S34F , indicating that RUNX1 loss is a mechanism of resistance. In conclusion, SRSF2 and U2AF1 mutations are biomarkers of sensitivity to ATR–CHK1 pathway inhibitors, while RUNX1 mutations cause resistance. These biomarkers can support patient stratification in MDS/AML.
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- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2025.10.06.680457
- https://www.biorxiv.org/content/biorxiv/early/2025/10/07/2025.10.06.680457.full.pdf
- OA Status
- green
- References
- 51
- OpenAlex ID
- https://openalex.org/W4414912717
All OpenAlex metadata
Raw OpenAlex JSON
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https://doi.org/10.1101/2025.10.06.680457Digital Object Identifier
- Title
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Sensitivity to ATR–CHK1 pathway inhibition in AML/MDS is enhanced by SRSF2 mutations and reduced by RUNX1 lossWork title
- Type
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preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2025Year of publication
- Publication date
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2025-10-07Full publication date if available
- Authors
-
Samuli Eldfors, Sumit Rai, V. D. Sharma, Tareq Hossan, Claudia Cabrera Pastrana, Amy M. Bertino, Angelique Gilbert, Kimmo Porkka, Matthew J. Walter, Timothy A. GraubertList of authors in order
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https://doi.org/10.1101/2025.10.06.680457Publisher landing page
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https://www.biorxiv.org/content/biorxiv/early/2025/10/07/2025.10.06.680457.full.pdfDirect link to full text PDF
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YesWhether a free full text is available
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greenOpen access status per OpenAlex
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https://www.biorxiv.org/content/biorxiv/early/2025/10/07/2025.10.06.680457.full.pdfDirect OA link when available
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