There is a pressing clinical need to develop novel treatments for patients with high-risk B-ALL, such as those harboring mutations in CREBBP. Using a highly-curated panel of clinically-tractable small molecules in an isogenic human cell line model, we demonstrate that CREBBP mutation sensitizes cells to Dexamethasone, inhibitors of residual CREBBP/EP300 function and most potently BCL2 inhibition. This evidence concerns the gene BCL2 and acute lymphoblastic leukemia.