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Wu HC, Rérolle D, Berthier C, et al. Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy. Cancer Discov. 2021;doi: 10.1158/2159-8290.CD-21-0177.
Wu, H. C., Rérolle, D., Berthier, C., Hleihel, R., Sakamoto, T., Quentin, S., Benhenda, S., Morganti, C., Wu, C., Conte, L., Rimsky, S., Sebert, M., Clappier, E., Souquere, S., Gachet, S., Soulier, J., Durand, S., Trowbridge, J. J., Bénit, P., Rustin, P., Hajj, H. E., Raffoux, E., Ades, L., Itzykson, R., Dombret, H., Fenaux, P., Espeli, O., Kroemer, G., Brunetti, L., Mak, T. W., Lallemand-Breitenbach, V., Bazarbachi, A., Falini, B., Ito, K., Martelli, M. P., & de Thé, H. (2021). Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy. Cancer discovery, . https://doi.org/10.1158/2159-8290.CD-21-0177
Wu, Hsin-Chieh, et al. "Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy." Cancer discovery vol. (2021). doi: https://doi.org/10.1158/2159-8290.CD-21-0177
Wu HC, Rérolle D, Berthier C, Hleihel R, Sakamoto T, Quentin S, Benhenda S, Morganti C, Wu C, Conte L, Rimsky S, Sebert M, Clappier E, Souquere S, Gachet S, Soulier J, Durand S, Trowbridge JJ, Bénit P, Rustin P, Hajj HE, Raffoux E, Ades L, Itzykson R, Dombret H, Fenaux P, Espeli O, Kroemer G, Brunetti L, Mak TW, Lallemand-Breitenbach V, Bazarbachi A, Falini B, Ito K, Martelli MP, de Thé H. Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy. Cancer Discov. 2021 Jul 23; doi: 10.1158/2159-8290.CD-21-0177. Epub 2021 Jul 23. PMID: 34301789.
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Cancer Discov. 2021 Jul 23; doi: 10.1158/2159-8290.CD-21-0177. Epub 2021 Jul 23.

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

Cancer discovery

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 Rustin, Hiba 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

Affiliations

  1. Collège de France, Oncologie Cellulaire et Moléculaire, PSL University, INSERM UMR 1050, CNRS UMR 7241, Paris, France.
  2. Université de Paris, INSERM U944, CNRS UMR 7212, IRSL, Hôpital St. Louis, Paris, France.
  3. Department of Internal Medicine and Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon.
  4. Department of Experimental Pathology, Microbiology and Immunology, American University of Beirut, Beirut, Lebanon.
  5. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  6. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  7. Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research and Departments of Cell Biology and Medicine, Albert Einstein College of Medicine, Bronx, New York.
  8. Department of Precision Medicine, University of Campania "Luigi Vanvitelli,?" Napoli, Italy.
  9. Department of Hematology, Hôpital Saint Louis (Assistance publique Hôpitaux de Paris) and Paris University, Paris, France.
  10. Institut Gustave Roussy, Cell Biology and Metabolomics Platforms, INSERM UMS 3655, Villejuif, France.
  11. The Jackson Laboratory, Bar Harbor, Maine.
  12. INSERM, U1141 Hôpital Robert Debré, Paris France.
  13. Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue Contre le Cancer, Université de Paris, Sorbonne Université, INSERM U1138, Institut Universitaire de France, Paris, France.
  14. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
  15. Collège de France, Oncologie Cellulaire et Moléculaire, PSL University, INSERM UMR 1050, CNRS UMR 7241, Paris, France. [email protected].

PMID: 34301789 DOI: 10.1158/2159-8290.CD-21-0177

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

©2021 The Authors; Published by the American Association for Cancer Research.

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