Reference - Detail
| RRC ID | 85100 |
|---|---|
| Author | Garcia-Gimenez A, Ditcham JE, Azazi DMA, Giotopoulos G, Asby R, Meduri E, Bagri J, Sakakini N, Lopez CK, Narayan N, Beinortas T, Agrawal-Singh S, Fung K, O'Connor D, Mansour MR, Alabed HBR, Jenkins B, Koulman A, Murphy MP, Horton SJ, Huntly BJP, Richardson SE. |
| Title | CREBBP inactivation sensitizes B cell acute lymphoblastic leukemia to ferroptotic cell death upon BCL2 inhibition. |
| Journal | Nat Commun |
| 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. |
| Volume | 16(1) |
| Pages | 4274 |
| Published | 2025-5-20 |
| DOI | 10.1038/s41467-025-59531-6 |
| PII | 10.1038/s41467-025-59531-6 |
| PMID | 40393984 |
| PMC | PMC12092839 |
| MeSH | Animals Antineoplastic Agents / pharmacology Apoptosis / drug effects Bridged Bicyclo Compounds, Heterocyclic / pharmacology CREB-Binding Protein* / antagonists & inhibitors CREB-Binding Protein* / genetics CREB-Binding Protein* / metabolism Cell Line, Tumor Drug Resistance, Neoplasm / drug effects Drug Resistance, Neoplasm / genetics Ferroptosis* / drug effects Ferroptosis* / genetics Humans Mice Mutation Precursor B-Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy Precursor B-Cell Lymphoblastic Leukemia-Lymphoma* / genetics Precursor B-Cell Lymphoblastic Leukemia-Lymphoma* / metabolism Precursor B-Cell Lymphoblastic Leukemia-Lymphoma* / pathology Proto-Oncogene Proteins c-bcl-2* / antagonists & inhibitors Proto-Oncogene Proteins c-bcl-2* / genetics Proto-Oncogene Proteins c-bcl-2* / metabolism Sulfonamides / pharmacology Xenograft Model Antitumor Assays |
| IF | 12.121 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | News |
| Total number of mentions | 37 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| DNA material | mCherry-hCdt1(30/120)/ pCSII-EF (RDB15273) mVenus-hGeminin(1/110) / pCSII-EF (RDB15271) |