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

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• TP53 mutations are a significant challenge in acute myeloid leukemia (AML) treatment, causing resistance to venetoclax.
• Venetoclax resistance is linked to TP53 mutations, but current stratification methods like variant allele frequency (VAF) are insufficient due to functional heterogeneity of TP53 mutants.

Purpose of the Study:

• To review the molecular mechanisms of TP53-mediated venetoclax resistance in AML.
• To highlight how specific TP53 mutations lead to distinct resistance phenotypes and therapeutic responses.
• To propose a framework integrating mutant-specific resistance biology for precision medicine.

Main Methods:

• Systematic review of recent advances in understanding TP53 mutation-driven venetoclax resistance.
• Analysis of molecular mechanisms including apoptotic dysregulation, metabolic reprogramming, leukemic stem cell enhancement, and epigenetic remodeling.
• Evaluation of current VAF-based classification limitations.

Main Results:

• TP53 mutants exhibit functional heterogeneity, resulting in diverse resistance mechanisms and phenotypes.
• Multiple pathways contribute to venetoclax resistance, with varying importance depending on the specific TP53 mutant.
• Conventional VAF stratification inadequately captures these complex resistance profiles.

Conclusions:

• Understanding mutant-specific TP53 biology is crucial for overcoming venetoclax resistance in AML.
• Precision therapeutic strategies tailored to individual TP53 mutation types are needed.
• A new classification framework integrating resistance mechanisms can guide treatment decisions.