TP53 mutations drive therapy resistance through post-mitochondrial caspase blockade.
7 affiliations
- 1Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, Singapore, Singapore.
- 2Department of Hematology & Medical Oncology, Emory School of Medicine and the Winship Cancer Institute, Emory University, Atlanta, GA, USA.
- 3Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
- 4Dana-Farber Cancer Institute, 440 Brookline Avenue, M430, Boston, MA, USA.
- 5Program in Cancer & Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
- 6Department of Pharmacy and Pharmaceutical Sciences, National University of Singapore, Singapore, Singapore. [email protected].
- 7Department of Hematology & Medical Oncology, Emory School of Medicine and the Winship Cancer Institute, Emory University, Atlanta, GA, USA. [email protected].
Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease characterized by a broad spectrum of molecular alterations that influence clinical outcomes. TP53 mutations define one of the most lethal subtypes of AML, driving resistance to nearly all available treatment modalities, including venetoclax plus azacitidine (VenAza). Yet, the molecular basis of this resistance, beyond affecting transactivation of BCL-2 family genes, has remained elusive. Here, we demonstrate that VenAza treatment leads to reduced transcriptional upregulation of the p53 signaling pathway in TP53 mutant/deficient AML compared to wild-type AML. Functionally, TP53 mutant/deficient AML exhibits selective failure in apoptosis induction rather than impaired G1 arrest or senescence. Despite inhibition of pro-apoptotic BAX and selective enrichment for MCL-1 in TP53 mutant isogenic AML cells, compensatory upregulation of BIM preserved functional mitochondrial outer membrane permeabilization (MOMP). TP53 mutant primary AML tumors at baseline also had retained capacity for MOMP. Instead, TP53 mutant AML exhibited disruption in caspase-3/7 activation to evade apoptosis after VenAza therapy - decoupling the mitochondrial and executioner phases of apoptosis. Importantly, this "post-MOMP brake" is not a bystander effect but itself a driver of VenAza and chemotherapy resistance in TP53 mutant/deficient AML. This previously unrecognized mechanistic insight shifts the focus from mitochondrial priming to terminal caspase blockade in TP53 mutant AML and opens the door for urgently needed therapeutic strategies that reignite apoptosis at its execution point.
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BibTeX
@article{mamdouh2026tp53,
title = {{TP53 mutations drive therapy resistance through post-mitochondrial caspase blockade.}},
author = {Ahmed M Mamdouh and Fizza Iftikhar and Elyse A Olesinski and Fang Qi Lim and Shaista Jasdanwala and Yuhan Wang and Yang Mi and Nicole Si En Lin and Daniel Tan En Liang and Md Al Nayem Chowdhury and Nishtha Chitkara and Leah Hogdal and Coleman R Lindsley and Anthony Letai and Koji Itahana and Shruti Bhatt},
journal = {Cell death \& disease},
year = {2026},
month = jul,
doi = {10.1038/s41419-026-09087-0},
url = {https://europepmc.org/article/MED/42918771},
note = {CC BY},
}
RIS
TY - JOUR
TI - TP53 mutations drive therapy resistance through post-mitochondrial caspase blockade.
AU - Ahmed M Mamdouh
AU - Fizza Iftikhar
AU - Elyse A Olesinski
AU - Fang Qi Lim
AU - Shaista Jasdanwala
AU - Yuhan Wang
AU - Yang Mi
AU - Nicole Si En Lin
AU - Daniel Tan En Liang
AU - Md Al Nayem Chowdhury
AU - Nishtha Chitkara
AU - Leah Hogdal
AU - Coleman R Lindsley
AU - Anthony Letai
AU - Koji Itahana
AU - Shruti Bhatt
PY - 2026
DA - 2026/07/01
JO - Cell death & disease
DO - 10.1038/s41419-026-09087-0
UR - https://europepmc.org/article/MED/42918771
AB - Acute myeloid leukemia (AML) is a heterogeneous disease characterized by a broad spectrum of molecular alterations that influence clinical outcomes. TP53 mutations define one of the most lethal subtypes of AML, driving resistance to nearly all available treatment modalities, including venetoclax plus azacitidine (VenAza). Yet, the molecular basis of this resistance, beyond affecting transactivation of BCL-2 family genes, has remained elusive. Here, we demonstrate that VenAza treatment leads to reduced transcriptional upregulation of the p53 signaling pathway in TP53 mutant/deficient AML compared to wild-type AML. Functionally, TP53 mutant/deficient AML exhibits selective failure in apoptosis induction rather than impaired G1 arrest or senescence. Despite inhibition of pro-apoptotic BAX and selective enrichment for MCL-1 in TP53 mutant isogenic AML cells, compensatory upregulation of BIM preserved functional mitochondrial outer membrane permeabilization (MOMP). TP53 mutant primary AML tumors at baseline also had retained capacity for MOMP. Instead, TP53 mutant AML exhibited disruption in caspase-3/7 activation to evade apoptosis after VenAza therapy - decoupling the mitochondrial and executioner phases of apoptosis. Importantly, this "post-MOMP brake" is not a bystander effect but itself a driver of VenAza and chemotherapy resistance in TP53 mutant/deficient AML. This previously unrecognized mechanistic insight shifts the focus from mitochondrial priming to terminal caspase blockade in TP53 mutant AML and opens the door for urgently needed therapeutic strategies that reignite apoptosis at its execution point.
SN - 2041-4889
ER -