Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy - Archive ouverte HAL Access content directly
Journal Articles Cancer Discovery Year : 2021

Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy

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

Abstract

Abstract Acute myeloid leukemia (AML) pathogenesis often involves a mutation in the NPM1 nucleolar chaperone, but the bases for its transforming properties and overall association 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 mitochondrial 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. This article is highlighted in the In This Issue feature, p. 2945

Dates and versions

hal-03829306 , version 1 (25-10-2022)

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Cite

Hsin-Chieh Wu, Domitille Rérolle, Caroline Berthier, Rita Hleihel, Takashi Sakamoto, et al.. Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy. Cancer Discovery, 2021, 11 (12), pp.3198-3213. ⟨10.1158/2159-8290.CD-21-0177⟩. ⟨hal-03829306⟩
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