Correction: Combined inhibition of BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance of TP53 -mutant acute myeloid leukemia to individual BH3 mimetics

TP53 -mutant acute myeloid leukemia (AML) respond poorly to currently available treatments, including venetoclax-based drug combinations and pose a major therapeutic challenge. Analyses of RNA sequencing and reverse phase protein array datasets revealed significantly lower BAX RNA and protein levels in TP53 -mutant compared to TP53– wild-type (WT) AML, a finding confirmed in isogenic CRISPR-generated TP53 -knockout and -mutant AML. The response to either BCL-2 (venetoclax) or MCL-1 (AMG176) inhibition was BAX-dependent and much reduced in TP53 -mutant compared to TP53 -WT cells, while the combination of two BH3 mimetics effectively activated BAX, circumventing survival mechanisms in cells treated with either BH3 mimetic, and synergistically induced cell death in TP53 -mutant AML and stem/progenitor cells. The BH3 mimetic–driven stress response and cell death patterns after dual inhibition were largely independent of TP53 status and affected by apoptosis induction. Co-targeting, but not individual targeting of BCL-2 and MCL-1 in mice xenografted with TP53 -WT and TP53 -R248W Molm13 cells suppressed both TP53 -WT and TP53 -mutant cell growth and significantly prolonged survival. Our results demonstrate that co-targeting BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance to individual BH3 mimetics in TP53 -mutant cells, thus shifting cell fate from survival to death in TP53 -deficient and -mutant AML. This concept warrants clinical evaluation.