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

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Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy
Cancer Discovery ( IF 28.2 ) Pub Date : 2021-12-01 , DOI: 10.1158/2159-8290.cd-21-0177
Hsin-Chieh Wu _{1,

2} , Domitille Rérolle _{1,

2} , Caroline Berthier _{1,

2} , Rita Hleihel _{1,

2,

3,

4} , Takashi Sakamoto _{5,

6} , Samuel Quentin ₂ , Shirine Benhenda ₂ , Claudia Morganti ₇ , Chengchen Wu _{1,

2} , Lidio Conte _{1,

2,

8} , Sylvie Rimsky ₁ , Marie Sebert _{2,

9} , Emmanuelle Clappier _{2,

9} , Sylvie Souquere ₁₀ , Stéphanie Gachet ₂ , Jean Soulier _{2,

9} , Sylvère Durand ₁₀ , Jennifer J Trowbridge ₁₁ , Paule Bénit ₁₂ , Pierre Rustin ₁₂ , Hiba El Hajj ₄ , Emmanuel Raffoux ₉ , Lionel Ades _{2,

9} , Raphael Itzykson _{2,

9} , Hervé Dombret ₉ , Pierre Fenaux _{2,

9} , Olivier Espeli ₁ , Guido Kroemer _{8,

13} , Lorenzo Brunetti ₁₄ , Tak W Mak ₆ , Valérie Lallemand-Breitenbach _{1,

2} , Ali Bazarbachi ₃ , Brunangelo Falini ₁₄ , Keisuke Ito ₇ , Maria Paola Martelli ₁₄ , Hugues de Thé _{1,

2,

9}

Affiliation

Collège de France, Oncologie Cellulaire et Moléculaire, PSL University, INSERM UMR 1050, CNRS UMR 7241, Paris, France.
Université de Paris, INSERM U944, CNRS UMR 7212, IRSL, Hôpital St. Louis, Paris, France.
Department of Internal Medicine and Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon.
Department of Experimental Pathology, Microbiology and Immunology, American University of Beirut, Beirut, Lebanon.
Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
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.
Department of Precision Medicine, University of Campania "Luigi Vanvitelli, " Napoli, Italy.
Department of Hematology, Hôpital Saint Louis (Assistance publique Hôpitaux de Paris) and Paris University, Paris, France.
Institut Gustave Roussy, Cell Biology and Metabolomics Platforms, INSERM UMS 3655, Villejuif, France.
The Jackson Laboratory, Bar Harbor, Maine.
INSERM, U1141 Hôpital Robert Debré, Paris France.
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.
Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.

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][1] [1]: /lookup/volpage/11/2945?iss=12

中文翻译：

Actinomycin D 靶向 NPM1c 引发的线粒体以恢复 AML 治疗中 PML 驱动的衰老

急性髓系白血病 (AML) 发病机制通常涉及 NPM1 核仁伴侣的突变，但其转化特性的基础以及与有利治疗反应的整体关联仍不完全清楚。在这里，我们证明 NPM1 (NPM1c) 的致癌突变形式会损害线粒体功能。NPM1c 还阻碍早幼粒细胞白血病 (PML) 核体 (NB) 的形成，核体是线粒体健康的调节因子和关键的衰老效应器。放线菌素 D (ActD) 是一种对复发/难治性 NPM1c-AML 具有明确临床疗效的抗生素，靶向这些已启动的线粒体，释放线粒体 DNA，激活环 GMP-AMP 合酶信号传导，并促进活性氧 (ROS) 的产生。后者恢复 PML NB 形成，驱动 TP53 激活和 NPM1c-AML 细胞衰老。在一些模型中，venetoclax 和 ActD 对线粒体的双重靶向协同作用，可清除 AML，并通过靶向 PML 来延长生存期。我们的研究揭示了 NPM1c 线粒体下游的意想不到的作用，并暗示线粒体/ROS/PML/TP53 衰老途径作为基于 ActD 的疗法的效应器。意义：ActD 可诱导 NPM1 突变 AML 完全缓解。我们发现 NPM1c 影响线粒体生物合成和 PML NB。ActD 以线粒体为目标，产生 ROS，促进 PML NB 生物发生并恢复衰老。ActD 和 Venetoclax 对线粒体的双重靶向显着增强了它们的体内抗 AML 活性。本文在本期专题中突出显示，[p. 11]。2945][1][1]：/lookup/volpage/11/2945?iss=12

更新日期：2021-12-02

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