TY - JOUR
T1 - Actinomycin d targets npm1c-primed mitochondria to restore pml-driven senescence in aml therapy
AU - Wu, Hsin Chieh
AU - Rérolle, Domitille
AU - Berthier, Caroline
AU - Hleihel, Rita
AU - Sakamoto, Takashi
AU - Quentin, Samuel
AU - Benhenda, Shirine
AU - Morganti, Claudia
AU - Wu, Chengchen
AU - Conte, Lidio
AU - Rimsky, Sylvie
AU - Sebert, Marie
AU - Clappier, Emmanuelle
AU - Souquere, Sylvie
AU - Gachet, Stéphanie
AU - Soulier, Jean
AU - Durand, Sylvère
AU - Trowbridge, Jennifer J.
AU - Bénit, Paule
AU - Rustin, Pierre
AU - Hajj, Hiba El
AU - Raffoux, Emmanuel
AU - Ades, Lionel
AU - Itzykson, Raphael
AU - Dombret, Hervé
AU - Fenaux, Pierre
AU - Espeli, Olivier
AU - Kroemer, Guido
AU - Brunetti, Lorenzo
AU - Mak, Tak W.
AU - Lallemand-Breitenbach, Valérie
AU - Bazarbachi, Ali
AU - Falini, Brunangelo
AU - Ito, Keisuke
AU - Martelli, Maria Paola
AU - de Thé, Hugues
N1 - Funding Information:
L. Adès reports consulting or advisory roles for BMS/Celgene and AbbVie and research funding from BMS/Celgene. R. Itzykson has received honoraria from AbbVie, Amgen, Astellas, BMS-Celgene, Daiichi-Sankyo, Jazz Pharmaceuticals, Karyopharm, Servier, and Stemline, and research funding from Janssen, Novartis, and Oncoethix (now Merck SD). A. Bazarbachi is on the speaker bureau or advisory board of Novartis, Roche, Sanofi, Jazz, Adienne, Astellas, Takeda, Hikma, Celgene, Janssen, MSD, AbbVie, Pfizer, and Amgen. B. Falini licensed a patent on NPM1 mutants (n. 102004901256449). B. Falini and M.P. Martelli declare honoraria from Rasna Therapeutics, Inc for scientific advisor activities. M.P. Martelli also declares consultancy at scientific advisory boards for AbbVie, Amgen, Celgene, Janssen, Novartis, Pfizer, and Jazz Pharmaceuticals, and honoraria from Amgen, Celgene, Janssen, and Novartis. L. Brunetti declares
Funding Information:
We warmly thank P.G. Pelicci for sharing mouse leukemia mod-els, V. Montcuquet for the animal husbandry, N. Setterblad and S. Duchez for the imaging and cytometry platforms, C. Vallot for bio-informatic advice, C. Bally for help with the patient samples, the 3P5 proteomic facility of Institut Cochin, the imaging ORION platform of Coll?ge de France for decisive help in PML NBs and mitochondrial alteration quantification, A. Mourier for discussions and advice, A. R?tig for DNA of mitochondria-depleted cells, M.H. Verlhac, E. Gilson, U. Sahin, J. Ablain, R. Rodriguez, C. Esnault, and other lab members for advice and comments on the manuscript. This work is dedicated to the first author?s late father Jung-Mao Wu and all those loved ones lost to COVID-19. Work in the Paris laboratories is supported by Coll?ge de France, INSERM, CNRS, University de Paris and University PSL, INCA [CAMELIA project, TRANSCAN (DRAMA project) and PLBIO19-198], Fondation du Coll?ge de France and Fonds Saint Michel, and the Sj?berg Award (to H. de Th?). This project has received funding from the European Research Council (ERC) under the European Union Horizon 2020 research and innovation program (Grant agreement n? 785917, PML-THERAPY). C. Morganti is supported by NYSTEM Einstein Training Program in Stem Cell Research. K. Ito and J.J. Trowbridge are supported by NIH grants, and K. Ito is a Leukemia Lymphoma Society Scholar. Work in Beyrouth and Perugia is supported by ERC grants (785917, 740230, 725725) and the ARC Foundation for Cancer Research (Leopold Griffuel Prize to B. Falini). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Funding Information:
We warmly thank P.G. Pelicci for sharing mouse leukemia models, V. Montcuquet for the animal husbandry, N. Setterblad and S. Duchez for the imaging and cytometry platforms, C. Vallot for bio-informatic advice, C. Bally for help with the patient samples, the 3P5 proteomic facility of Institut Cochin, the imaging ORION platform of Collège de France for decisive help in PML NBs and mitochondrial alteration quantification, A. Mourier for discussions and advice, A. Rötig for DNA of mitochondria-depleted cells, M.H. Verlhac, E. Gilson, U. Sahin, J. Ablain, R. Rodriguez, C. Esnault, and other lab members for advice and comments on the manuscript. This work is dedicated to the first author’s late father Jung-Mao Wu and all those loved ones lost to COVID-19. Work in the Paris laboratories is supported by Collège de France, INSERM, CNRS, University de Paris and University PSL, INCA [CAMELIA project, TRANSCAN (DRAMA project) and PLBIO19-198], Fondation du Collège de France and Fonds Saint Michel, and the Sjöberg Award (to H. de Thé). This project has received funding from the European Research Council (ERC) under the European Union Horizon 2020 research and innovation program (Grant agreement n° 785917, PML-THERAPY). C. Morganti is supported by NYSTEM Einstein Training Program in Stem Cell Research. K. Ito and J.J. Trowbridge are supported by NIH grants, and K. Ito is a Leukemia Lymphoma Society Scholar. Work in Beyrouth and Perugia is supported by ERC grants (785917, 740230, 725725) and the ARC Foundation for Cancer Research (Leopold Griffuel Prize to B. Falini).
Publisher Copyright:
© 2021 The Authors; Published by the American Association for Cancer Research.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85116985389&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85116985389&partnerID=8YFLogxK
U2 - 10.1158/2159-8290.CD-21-0177
DO - 10.1158/2159-8290.CD-21-0177
M3 - Article
C2 - 34301789
AN - SCOPUS:85116985389
VL - 11
SP - 3198
EP - 3213
JO - Cancer Discovery
JF - Cancer Discovery
SN - 2159-8274
IS - 12
ER -