CREBBP inactivation sensitizes B cell acute lymphoblastic leukemia to ferroptotic cell death upon BCL2 inhibition
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 incr...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-59531-6 |
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| author | 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 Simon E. Richardson |
| author_facet | 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 Simon E. Richardson |
| author_sort | Alicia Garcia-Gimenez |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-dbf4ab90906c4dfda7f0cfd40de23b87 |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-dbf4ab90906c4dfda7f0cfd40de23b872025-08-20T01:53:14ZengNature PortfolioNature Communications2041-17232025-05-0116112110.1038/s41467-025-59531-6CREBBP inactivation sensitizes B cell acute lymphoblastic leukemia to ferroptotic cell death upon BCL2 inhibitionAlicia Garcia-Gimenez0Jonathan E. Ditcham1Dhoyazan M. A. Azazi2George Giotopoulos3Ryan Asby4Eshwar Meduri5Jaana Bagri6Nathalie Sakakini7Cecile K. Lopez8Nisha Narayan9Tumas Beinortas10Shuchi Agrawal-Singh11Kent Fung12David O’Connor13Marc R. Mansour14Husam B. R. Alabed15Benjamin Jenkins16Albert Koulman17Michael P. Murphy18Sarah J. Horton19Brian J. P. Huntly20Simon E. Richardson21Department of Haematology, Cambridge Stem Cell InstituteDepartment of Haematology, Cambridge Stem Cell InstituteDepartment of Haematology, Cambridge Stem Cell InstituteDepartment of Haematology, Cambridge Stem Cell InstituteDepartment of Haematology, Cambridge Stem Cell InstituteDepartment of Haematology, Cambridge Stem Cell InstituteDepartment of Haematology, Cambridge Stem Cell InstituteDepartment of Haematology, Cambridge Stem Cell InstituteDepartment of Haematology, Cambridge Stem Cell InstituteDepartment of Haematology, Cambridge Stem Cell InstituteDepartment of Haematology, Cambridge Stem Cell InstituteDepartment of Haematology, Cambridge Stem Cell InstituteUniversity College London Cancer Institute, UCLUniversity College London Cancer Institute, UCLUniversity College London Cancer Institute, UCLInstitute of Metabolic Science, University of CambridgeInstitute of Metabolic Science, University of CambridgeInstitute of Metabolic Science, University of CambridgeMRC Mitochondrial Biology Unit, Keith Peters Building, University of CambridgeDepartment of Haematology, Cambridge Stem Cell InstituteDepartment of Haematology, Cambridge Stem Cell InstituteDepartment of Haematology, Cambridge Stem Cell InstituteAbstract 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.https://doi.org/10.1038/s41467-025-59531-6 |
| spellingShingle | 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 Simon E. Richardson CREBBP inactivation sensitizes B cell acute lymphoblastic leukemia to ferroptotic cell death upon BCL2 inhibition Nature Communications |
| title | CREBBP inactivation sensitizes B cell acute lymphoblastic leukemia to ferroptotic cell death upon BCL2 inhibition |
| title_full | CREBBP inactivation sensitizes B cell acute lymphoblastic leukemia to ferroptotic cell death upon BCL2 inhibition |
| title_fullStr | CREBBP inactivation sensitizes B cell acute lymphoblastic leukemia to ferroptotic cell death upon BCL2 inhibition |
| title_full_unstemmed | CREBBP inactivation sensitizes B cell acute lymphoblastic leukemia to ferroptotic cell death upon BCL2 inhibition |
| title_short | CREBBP inactivation sensitizes B cell acute lymphoblastic leukemia to ferroptotic cell death upon BCL2 inhibition |
| title_sort | crebbp inactivation sensitizes b cell acute lymphoblastic leukemia to ferroptotic cell death upon bcl2 inhibition |
| url | https://doi.org/10.1038/s41467-025-59531-6 |
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