Enhanced TP53 Reactivation Disrupts MYC Transcriptional Program and Overcomes Venetoclax Resistance in Acute Myeloid Leukemias

Authors

Yuki Nishida
Jo Ishizawa
Edward Ayoub
Rafael Heinz Montoya
Lauren B Ostermann
Muharrem Muftuoglu
Vivian R Ruvolo
Tallie Patsilevas
Darah A Scruggs
Shayaun Khazaei
Po Yee Mak
Wenjing Tao
Bing Z Carter
Steffen Boettcher
Benjamin L Ebert
Naval G Daver
Marina Konopleva
Takahiko Seki
Kensuke Kojima
Michael Andreeff

Publication Date

12-1-2023

Journal

Science Advances

Abstract

The tumor suppressor TP53 is frequently inactivated in a mutation-independent manner in cancers and is reactivated by inhibiting its negative regulators. We here cotarget MDM2 and the nuclear exporter XPO1 to maximize transcriptional activity of p53. MDM2/XPO1 inhibition accumulated nuclear p53 and elicited a 25- to 60-fold increase of its transcriptional targets. TP53 regulates MYC, and MDM2/XPO1 inhibition disrupted the c-MYC-regulated transcriptome, resulting in the synergistic induction of apoptosis in acute myeloid leukemia (AML). Unexpectedly, venetoclax-resistant AMLs express high levels of c-MYC and are vulnerable to MDM2/XPO1 inhibition in vivo. However, AML cells persisting after MDM2/XPO1 inhibition exhibit a quiescence- and stress response-associated phenotype. Venetoclax overcomes that resistance, as shown by single-cell mass cytometry. The triple inhibition of MDM2, XPO1, and BCL2 was highly effective against venetoclax-resistant AML in vivo. Our results propose a novel, highly translatable therapeutic approach leveraging p53 reactivation to overcome nongenetic, stress-adapted venetoclax resistance.

Keywords

Humans, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-mdm2, Cell Line, Tumor, Leukemia, Myeloid, Acute, Apoptosis

Comments

Supplementary Material

PMID: 38019903

DOI

10.1126/sciadv.adh1436

PMID

38019903

PMCID

PMC10686564

PubMedCentral® Posted Date

November 2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes