TY - JOUR
T1 - CREBBP inactivation sensitizes B cell acute lymphoblastic leukemia to ferroptotic cell death upon BCL2 inhibition
AU - Garcia-Gimenez, Alicia
AU - Ditcham, Jonathan E.
AU - Azazi, Dhoyazan M.A.
AU - Giotopoulos, George
AU - Asby, Ryan
AU - Meduri, Eshwar
AU - Bagri, Jaana
AU - Sakakini, Nathalie
AU - Lopez, Cecile K.
AU - Narayan, Nisha
AU - Beinortas, Tumas
AU - Agrawal-Singh, Shuchi
AU - Fung, Kent
AU - O’Connor, David
AU - Mansour, Marc R.
AU - Alabed, Husam B.R.
AU - Jenkins, Benjamin
AU - Koulman, Albert
AU - Murphy, Michael P.
AU - Horton, Sarah J.
AU - Huntly, Brian J.P.
AU - Richardson, Simon E.
N1 - Publisher Copyright:
© The Author(s) 2025.
PY - 2025/5/20
Y1 - 2025/5/20
N2 - 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.
AB - 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.
KW - Humans
KW - Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors
KW - Bridged Bicyclo Compounds, Heterocyclic/pharmacology
KW - CREB-Binding Protein/genetics
KW - Cell Line, Tumor
KW - Sulfonamides/pharmacology
KW - Ferroptosis/drug effects
KW - Drug Resistance, Neoplasm/drug effects
KW - Animals
KW - Mice
KW - Mutation
KW - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics
KW - Antineoplastic Agents/pharmacology
KW - Apoptosis/drug effects
KW - Xenograft Model Antitumor Assays
UR - http://www.scopus.com/inward/record.url?scp=105005545230&partnerID=8YFLogxK
U2 - 10.1038/s41467-025-59531-6
DO - 10.1038/s41467-025-59531-6
M3 - Article
C2 - 40393984
AN - SCOPUS:105005545230
SN - 2041-1723
VL - 16
SP - 4274
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4274
ER -