TP53 mutations drive therapy resistance via post-mitochondrial caspase blockade

Area of Science:

• Hematology
• Molecular Biology
• Cancer Research

Background:

• Acute myeloid leukemia (AML) is a complex blood cancer with varied molecular drivers.
• TP53 mutations are linked to poor prognosis and treatment resistance in AML, particularly to Venetoclax plus Azacitidine (VenAza).
• The precise mechanisms of VenAza resistance in TP53-mutant AML remain incompletely understood.

Purpose of the Study:

• To investigate the molecular basis of Venetoclax plus Azacitidine (VenAza) resistance in TP53-mutant/deficient acute myeloid leukemia (AML).
• To elucidate the functional consequences of TP53 mutations on apoptosis induction pathways in AML cells.
• To identify novel therapeutic strategies targeting VenAza resistance in TP53-mutant AML.

Main Methods:

• Comparative analysis of p53 signaling pathway activation in TP53-mutant versus wild-type AML cells upon VenAza treatment.
• Functional assays assessing G1 arrest, senescence, and apoptosis induction in isogenic AML models.
• Evaluation of mitochondrial outer membrane permeabilization (MOMP) and caspase-3/7 activation.
• Assessment of TP53-mutant primary AML tumors.

Main Results:

• TP53-mutant/deficient AML shows reduced p53 pathway upregulation and impaired apoptosis induction after VenAza treatment.
• While MOMP is preserved, TP53-mutant AML exhibits defective caspase-3/7 activation, decoupling apoptosis phases.
• This caspase blockade is a key driver of VenAza and chemotherapy resistance in TP53-mutant AML.
• TP53-mutant AML cells demonstrate selective failure in apoptosis rather than cell cycle arrest.

Conclusions:

• Resistance to VenAza in TP53-mutant AML is primarily driven by a post-MOMP blockade of caspase activation.
• This mechanism highlights terminal caspase activation as a critical vulnerability in TP53-mutant AML.
• Targeting caspase activation offers a promising therapeutic avenue to overcome VenAza resistance in this lethal AML subtype.