Functional heterogeneity of TP53 mutants in venetoclax-resistant AML: mechanisms, clinical implications, and therapeutic opportunities.

TP53 mutations are strongly associated with resistance to venetoclax in acute myeloid leukemia (AML) and represent a major challenge in current treatment strategies. Importantly, different TP53 mutants exhibit substantial functional heterogeneity, leading to distinct resistance phenotypes that are not adequately captured by conventional variant allele frequency (VAF)-based stratification. Emerging evidence suggests that TP53 mutations promote venetoclax resistance through multiple mechanisms, including apoptotic dysregulation, metabolic reprogramming, enhancement of leukemic stem cell properties, and epigenetic remodeling, with the relative contribution of each pathway varying among mutant types. This review systematically summarizes recent advances in the molecular mechanisms underlying TP53-mediated venetoclax resistance, with a particular focus on how mutant-specific functional differences shape therapeutic responses. Unlike previous broad reviews of TP53-mutated AML, this article specifically addresses venetoclax resistance as a clinically critical therapeutic challenge. We further discuss the limitations of current VAF-based classification systems and propose a practical framework that integrates mutant-specific resistance biology with precision therapeutic strategies.