ArticleCancer discovery2021
Actinomycin D Targets NPM1c-Primed Mitochondria to Restore PML-Driven Senescence in AML Therapy.
Article in Cancer discovery, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 71 citations in OpenAlex.
- The Relationship Between Immunogenic Cell Death and Cellular Senescence in Cancer Immunotherapy.Life (Basel, Switzerland) · 2026Review
- Advanced drug delivery platforms targeting cellular senescence: A promising strategy for cancer therapy.Acta pharmaceutica Sinica. B · 2026Review
- Disproportionality Analysis of Hematologic Adverse Event Signals Associated with Venetoclax in Combination with Senescence-Inducing Chemotherapy.Journal of clinical medicine · 2026Article
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- Metabolism and HSC fate: what NADPH is made for.Trends in cell biology · 2025Review
- Mitochondrial metabolism and cancer therapeutic innovation.Signal transduction and targeted therapy · 2025Review
- NRF2 maintains redox balance via ME1 and NRF2 inhibitor synergizes with venetoclax in NPM1-mutated acute myeloid leukemia.Cancer & metabolism · 2025Article
- PSMB10 maintains the stemness of chemotherapeutic drug-resistant leukemia cells by inhibiting senescence and cytotoxic T lymphocyte-mediated killing in a ubiquitinated degradation manner.Journal of experimental & clinical cancer research : CR · 2025Article
- Influence of Nucleophosmin (Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2025Article
- Conventional chemotherapy: millions of cures, unresolved therapeutic index.Nature reviews. Cancer · 2025Review
- Preclinical Assessment of Dactinomycin inCancers · 2025Article
- Article
- PML Nuclear bodies: the cancer connection and beyond.Nucleus (Austin, Tex.) · 2024Review
- Immunotherapeutic Potential of Mutated NPM1 for the Treatment of Acute Myeloid Leukemia.Cancers · 2024Review
- Article
- Acute Promyelocytic Leukemia, Retinoic Acid, and Arsenic: A Tale of Dualities.Cold Spring Harbor perspectives in medicine · 2024Review
- Review
- KRAS-mutant non-small cell lung cancer (NSCLC) therapy based on tepotinib and omeprazole combination.Cell communication and signaling : CCS · 2024Article
- Oxidative stress is two-sided in the treatment of acute myeloid leukemia.Cancer medicine · 2024Review
Corrections and comments
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Authors and funding
36 authors at 9 institutions in 6 countries.
Funding
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 in vivo. This article is highlighted in the In This Issue feature, p. 2945.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.