Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy.
Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy.
复制标题
DOI：
10.1158/2159-8290.cd-21-0177
复制
发表时间：
2021-12-01
期刊：
影响因子：
28.2
通讯作者：
de Thé H
中科院分区：
文献类型：
--
作者：
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;El Hajj H;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
致癌性NPM1c突变为放线菌素D的线粒体靶向急性髓系白血病细胞提供了初始条件，从而恢复PML核小体驱动的衰老，并与venetoclax协同诱导肿瘤清除。急性髓性白血病（AML）的发病机制通常涉及NPM1核核伴侣蛋白的突变，但其转化特性的基础以及与良好治疗反应的总体关联仍不完全清楚。在这里，我们证明了NPM1的致癌突变形式（NPM1c）损害线粒体功能。NPM1c还阻碍早幼粒细胞白血病（PML）核小体（NB）的形成，而核小体是线粒体适应性的调节因子和关键的衰老效应因子。放线菌素D （ActD）是一种对复发/难治性NPM1c-AMLs具有明确临床疗效的抗生素，靶向这些引物线粒体，释放线粒体DNA，激活环GMP-AMP合成酶信号，并促进活性氧（ROS）的产生。后者恢复PML NB的形成，从而驱动TP53的激活和NPM1c-AML细胞的衰老。在一些模型中，venetoclax和ActD双重靶向线粒体协同清除AML并通过靶向PML延长生存期。我们的研究揭示了线粒体在NPM1c下游的意想不到的作用，并暗示线粒体/ROS/PML/TP53衰老途径是基于actd的治疗的效应。ActD诱导npm1突变AMLs完全缓解。我们发现NPM1c影响线粒体生物发生和PML NBs。ActD靶向线粒体，产生ROS，促进PML NB生物发生，恢复衰老。ActD和venetoclax在体内双重靶向线粒体可显著增强其抗aml活性。这篇文章在“本期专题”第2945页突出显示
Oncogenic NPM1c mutations prime acute myeloid leukemia cells for mitochondrial targeting by actinomycin D, which restores PML nuclear bodies—driven senescence and is synergistic with venetoclax to induce tumor clearance. 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. 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