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

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 associate with high-risk features in B-ALL and have been implicated in chemoresistance. We performed a targeted drug screen in isogenic human cell lines, identifying a number of actionable small molecules that specifically target CREBBP -mutated B-ALL. The most potent was the BCL2 inhibitor Venetoclax, which acts through a non-canonical mechanism resulting in ferroptotic cell death. CREBBP -mutated cell lines showed differences in cell-cycle, metabolism and response to oxidative stress. Lastly, we demonstrate that small-molecule inhibition of CREBBP sensitizes 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. ### Competing Interest Statement NN is a former employee of the Walter and Eliza Hall Institute which receives milestone and royalty payments related to venetoclax. NN received payments from WEHI related to venetoclax.