TP53突变的急性髓系白血病（AML）对当前可用的治疗，包括基于威利托克赛的药物联合疗法反应不佳，并构成了重大的治疗挑战。RNA测序和逆向相位蛋白质阵列数据集的分析显示，与TP53野生型（WT）AML相比，TP53突变的BAX RNA和蛋白水平明显降低，这一发现在同源CRISPR产生的TP53敲除和突变AML中得到了证实。BCL-2（威利托克赛）或MCL-1（AMG176）抑制的反应取决于BAX，并且与TP53 WT细胞相比，TP53突变细胞的抑制作用大大降低，而两种BH3类拟合剂的组合有效地激活BAX，在任何接受BH3拟合剂治疗的细胞中绕过了生存机制，并在TP53突变AML和干/祖细胞中协同诱导细胞死亡。在双重抑制后，BH3类拟合剂驱动的应激反应和细胞死亡模式在很大程度上与TP53状态无关，受到凋亡诱导的影响。在小鼠移植TP53 WT和TP53-R248W Molm13细胞的实验中，共同靶向BCL-2和MCL-1抑制了TP53 WT和TP53突变细胞的生长并显著延长了存活时间。我们的结果表明，在TP53突变细胞中，共同靶向BCL-2和MCL-1克服了BAX缺乏介导的对单一BH3类拟合剂的抵抗，从而在TP53缺陷和突变AML中将细胞命运从生存转向死亡。这个概念值得进行临床评估。©2023年作者。

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.© 2023. The Author(s).