Genetic or pharmacological inactivation of CREBBP sensitizes B-cell Acute Lymphoblastic Leukemia to Ferroptotic Cell Death upon BCL2 Inhibition [CUT&RUN]

B-cell acute lymphoblasTc 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. MutaTons in the histone acetyltransferase CREBBP confer high-risk and increased chemoresistance in ALL. Performing a targeted drug-screen in isogenic human cell lines, we idenTfied a number of small molecules that specifically targeted CREBBP-mutated B-ALL, with the most potent the BCL2-inhibitor Venetoclax. Of note, this acted through a non-canonical mechanism resulTng in ferroptoTc rather than apoptoTc cell death. CREBBP-mutated cell lines showed differences in cell- cycle, metabolism, lipid composiTon and response to oxidaTve stress, predisposing them to ferroptosis, which were further dysregulated upon acquisiTon of Venetoclax resistance. Lastly, small- molecule inhibiTon of CREBBP pharmacocopies CREBBP-mutaTon, sensiTzing B-ALL cells, regardless of genotype, to Venetoclax-induced ferroptosis in-vitro and in-vivo, providing a potential novel drug combination for broader clinical translation in B-ALL.