Actinomycin D targets NPM1c-primed mitochondria to restore PML-driven senescence in AML therapy.

Hsin-Chieh Wu
Domitille Rerolle
Caroline Berthier
Rita Hleihel
Takashi Sakamoto
Samuel Quentin
Shirine Benhenda
Claudia Morganti
Chengchen Wu
Lidio Conte
Sylvie Rimsky
Marie Sebert
Emmanuelle Clappier
Sylvie Souquere
Stephanie Gachet
Jean Soulier
Sylvere Durand
Jennifer J. Trowbridge, The Jackson Laboratory
Paule Benit
Pierre Rustin
Hiba El Hajj
Emmanuel Raffoux
Lionel Ades
Raphael Itzykson
Herve Dombret
Pierre Fenaux
Olivier Espeli
Guido Kroemer
Lorenzo Brunetti
Tak W Mak
Valerie Lallemand-Breitenbach
Ali Bazarbachi
Brunangelo Falini
Keisuke Ito
Maria Paola Martelli
Hugues de The


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 PML nuclear bodies (NBs), 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 mtDNA, activating cGAS signaling and boosting 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.