CREBBP inactivation sensitizes B cell acute lymphoblastic leukemia to ferroptotic cell death upon BCL2 inhibition
B-cell acute lymphoblastic leukemia (B-ALL) is a leading cause of death in childhood and outcomes in adults remain dismal. There is therefore an urgent clinical need for therapies that target the highest risk cases. Mutations in the histone acetyltransferase CREBBP confer high-risk and increased chemoresistance in ALL. Performing a targeted drug-screen in isogenic human cell lines, we identify a number of small molecules that specifically target CREBBP-mutated B-ALL, the most potent being the BCL2-inhibitor Venetoclax. Of note, this acts through a non-canonical mechanism resulting in ferroptotic rather than apoptotic cell death. CREBBP-mutated cell lines show differences in cell-cycle, metabolism, lipid composition and response to oxidative stress, predisposing them to ferroptosis, which are further dysregulated upon acquisition of Venetoclax resistance. Lastly, small-molecule inhibition of CREBBP pharmacocopies CREBBP-mutation, sensitizing B-ALL cells, regardless of genotype, to Venetoclax-induced ferroptosis in-vitro and in-vivo, providing a promising drug combination for broader clinical translation in B-ALL.
Authors
- Sarah J. Horton (ORCID: https://orcid.org/0000-0001-8418-5783)
- Albert Koulman (ORCID: https://orcid.org/0000-0001-9998-051X)
- George Giotopoulos (ORCID: https://orcid.org/0000-0003-1390-6592)
- Benjamin Jenkins (ORCID: https://orcid.org/0000-0003-0038-9709)
- Dhoyazan Azazi (ORCID: https://orcid.org/0000-0001-9085-4031)
- Brian J.P. Huntly (ORCID: https://orcid.org/0000-0003-0312-161X)
- Tumas Beinortas (ORCID: https://orcid.org/0000-0002-2621-5494)
- Jaana Bagri (ORCID: https://orcid.org/0000-0002-2450-8226)
- Ryan Asby (ORCID: https://orcid.org/0000-0001-5077-3798)
- Kent Fung (ORCID: https://orcid.org/0000-0002-5797-1268)
- Cécile K. Lopez (ORCID: https://orcid.org/0000-0003-4473-6311)
- Husam B. R. Alabed (ORCID: https://orcid.org/0000-0002-9229-088X)
- Michael P. Murphy (ORCID: https://orcid.org/0000-0003-1115-9618)
- Shuchi Agrawal‐Singh (ORCID: https://orcid.org/0000-0001-8632-4556)
- David O’Connor (ORCID: https://orcid.org/0000-0003-3542-5976)
- Eshwar Meduri (ORCID: https://orcid.org/0000-0002-3821-312X)
- Marc R. Mansour (ORCID: https://orcid.org/0000-0001-6835-3791)
- Nisha Narayan (ORCID: https://orcid.org/0000-0002-4106-2166)
- Simon Richardson (ORCID: https://orcid.org/0000-0003-4343-4784)
- Jonathan E. Ditcham
- Alícia Giménez (ORCID: https://orcid.org/0000-0003-0604-3215)
- Nathalie Sakakini
Institutions
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- University of Cambridge (GB)
- University of Perugia (IT)
- Great Ormond Street Hospital (GB)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Bridge University (SS)
- CRUK Lung Cancer Centre of Excellence (GB)
- University College London (GB)
- Imperial College London (GB)
- MRC Mitochondrial Biology Unit (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-20
- DOI
- https://doi.org/10.1038/s41467-025-59531-6
- Citations
- 6
- Primary Topic
- Drug Transport and Resistance Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 6.27
Funders
- Wellcome Trust
- Cancer Research UK
- National Institute for Health and Care Research
- Department of Health and Social Care
- Isaac Newton Trust
- Blood Cancer UK
- Medical Research Council
- Cambridge Institute for Medical Research, University of Cambridge
- RIKEN
- NIHR Cambridge Biomedical Research Centre