Actinomycin d targets npm1c-primed mitochondria to restore pml-driven senescence in aml therapy

Hsin Chieh Wu, Domitille Rérolle, Caroline Berthier, Rita Hleihel, Takashi Sakamoto, Samuel Quentin, Shirine Benhenda, Claudia Morganti, Chengchen Wu, Lidio Conte, Sylvie Rimsky, Marie Sebert, Emmanuelle Clappier, Sylvie Souquere, Stéphanie Gachet, Jean Soulier, Sylvère Durand, Jennifer J. Trowbridge, Paule Bénit, Pierre RustinHiba El Hajj, Emmanuel Raffoux, Lionel Ades, Raphael Itzykson, Hervé Dombret, Pierre Fenaux, Olivier Espeli, Guido Kroemer, Lorenzo Brunetti, Tak W. Mak, Valérie Lallemand-Breitenbach, Ali Bazarbachi, Brunangelo Falini, Keisuke Ito, Maria Paola Martelli, Hugues de Thé

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Acute myeloid leukemia (AML) pathogenesis often involves a mutation in the NPM1 nucleolar chaperone, but the bases for its transforming properties and overall asso-ciation with favorable therapeutic responses remain incompletely understood. Here we demonstrate that an oncogenic mutant form of NPM1 (NPM1c) impairs mitochondrial function. NPM1c also hampers formation of promyelocytic leukemia (PML) nuclear bodies (NB), which are regulators of mitochondrial fitness and key senescence effectors. Actinomycin D (ActD), an antibiotic with unambiguous clinical efficacy in relapsed/refractory NPM1c-AMLs, targets these primed mitochondria, releasing mito-chondrial DNA, activating cyclic GMP-AMP synthase signaling, and boosting reactive oxygen species (ROS) production. The latter restore PML NB formation to drive TP53 activation and senescence of NPM1c-AML cells. In several models, dual targeting of mitochondria by venetoclax and ActD synergized to clear AML and prolong survival through targeting of PML. Our studies reveal an unexpected role for mitochondria downstream of NPM1c and implicate a mitochondrial/ROS/PML/TP53 senescence pathway as an effector of ActD-based therapies. SIGNIFICANCE: ActD induces complete remissions in NPM1-mutant AMLs. We found that NPM1c affects mitochondrial biogenesis and PML NBs. ActD targets mitochondria, yielding ROS which enforce PML NB biogenesis and restore senescence. Dual targeting of mitochondria with ActD and venetoclax sharply potentiates their anti-AML activities in vivo.

Original languageEnglish (US)
Pages (from-to)3198-3213
Number of pages16
JournalCancer discovery
Volume11
Issue number12
DOIs
StatePublished - 2021

ASJC Scopus subject areas

  • Oncology

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