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.
TP53突变的急性髓系白血病（AML）对包括基于维奈托克联合疗法在内的现有治疗方案反应不佳，构成了重大的治疗挑战。通过RNA测序及反相蛋白阵列数据分析发现，与TP53野生型AML相比，TP53突变型AML中BAX的RNA及蛋白水平显著降低，这一发现在经CRISPR技术构建的同基因TP53敲除及突变型AML模型中得以验证。在TP53突变型细胞中，针对BCL-2（维奈托克）或MCL-1（AMG176）抑制剂的治疗反应呈现BAX依赖性，且疗效较TP53野生型细胞显著减弱；而联合使用两种BH3模拟药物能有效激活BAX，规避单用BH3模拟药物时的细胞存活机制，并在TP53突变型AML及其干细胞/祖细胞中产生协同促死亡效应。双重抑制后由BH3模拟药物驱动的应激反应与细胞死亡模式在很大程度上独立于TP53状态，主要受凋亡诱导影响。在移植TP53野生型及TP53-R248W突变型Molm13细胞的小鼠模型中，同时靶向BCL-2与MCL-1（而非单独靶向）能同时抑制TP53野生型与突变型细胞生长，并显著延长生存期。我们的研究结果表明，在TP53突变细胞中同时靶向BCL-2与MCL-1可克服由BAX缺陷介导的单药BH3模拟药物耐药性，从而将TP53缺陷及突变型AML的细胞命运从生存导向死亡。这一治疗理念值得进行临床评估。
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