CREBBP inactivation sensitizes B cell acute lymphoblastic leukemia to ferroptotic cell death upon BCL2 inhibition

Alicia Garcia-Gimenez, Jonathan E. Ditcham, Dhoyazan M. A. Azazi, George Giotopoulos, Ryan Asby, Eshwar Meduri, Jaana Bagri, Nathalie Sakakini, Cecile K. Lopez, Nisha Narayan, Tumas Beinortas, Shuchi Agrawal-Singh, Kent Fung, David O’Connor, Marc R. Mansour, Husam B. R. Alabed, Benjamin Jenkins, Albert Koulman, Michael P. Murphy, Sarah J. Horton, Brian J. P. Huntly () and Simon E. Richardson ()
Additional contact information
Alicia Garcia-Gimenez: Cambridge Stem Cell Institute
Jonathan E. Ditcham: Cambridge Stem Cell Institute
Dhoyazan M. A. Azazi: Cambridge Stem Cell Institute
George Giotopoulos: Cambridge Stem Cell Institute
Ryan Asby: Cambridge Stem Cell Institute
Eshwar Meduri: Cambridge Stem Cell Institute
Jaana Bagri: Cambridge Stem Cell Institute
Nathalie Sakakini: Cambridge Stem Cell Institute
Cecile K. Lopez: Cambridge Stem Cell Institute
Nisha Narayan: Cambridge Stem Cell Institute
Tumas Beinortas: Cambridge Stem Cell Institute
Shuchi Agrawal-Singh: Cambridge Stem Cell Institute
Kent Fung: UCL
David O’Connor: UCL
Marc R. Mansour: UCL
Husam B. R. Alabed: University of Cambridge
Benjamin Jenkins: University of Cambridge
Albert Koulman: University of Cambridge
Michael P. Murphy: University of Cambridge
Sarah J. Horton: Cambridge Stem Cell Institute
Brian J. P. Huntly: Cambridge Stem Cell Institute
Simon E. Richardson: Cambridge Stem Cell Institute

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59531-6

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