Unlabelled: 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.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612574 | PMC |
http://dx.doi.org/10.1158/2159-8290.CD-21-0177 | DOI Listing |
Cancer Treat Rev
December 2024
SOLTI Cancer Research Group, Barcelona, Spain; Statistics Unit, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. Electronic address:
Introduction: Antibody-drug conjugates (ADCs) trastuzumab-deruxtecan (T-DXd) and sacituzumab-govitecan (SG) provided significant progression-free survival (PFS) and overall survival (OS) improvements over chemotherapy (CT) in pretreated hormone receptor-positive (HR+) and triple-negative (TN)/HER2-low metastatic breast cancer (MBC). However, no direct comparison between the two exists, nor with the more recent datopotamab-deruxtecan (Dato-DXd).
Methods: We conducted a network meta-analysis (NMA) to compare efficacy and safety of T-DXd and SG in CT-pretreated HR+ and TN/HER2-low MBC and assess their benefit over standard CT, exploring also a comparison with Dato-DXd.
Expert Opin Pharmacother
December 2024
Department of Metabolic Medicine/Chemical Pathology Guy's & St Thomas' Hospitals, London, UK.
Introduction: Lipid-lowering therapies are well established for the treatment of cardiovascular disease (CVD). Historically monotherapy studies were performed but the introduction of statins has led to these drugs being recognized as baseline therapies and to the investigation of combination therapy of both older and newer medications with them.
Areas Covered: Surrogate marker studies have shown additive effects on LDL-C, triglycerides and HDL-C of combination therapies with statins and these have extended to lipoprotein (a).
Discov Oncol
December 2024
Department of Radiotherapy, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China.
High expression of immune checkpoint molecule B7-H3 (CD276) in many cancer types makes it a promising immunotherapeutic target. Both coinhibitory and costimulatory effects of B7-H3 in tumors have been demonstrated, but the mechanism of B7-H3 immune response under dual effects is open to question. B7-H3 is crucially involved in the migration and invasion, angiogenesis, metabolism and chemotherapy resistance of prostate cancer.
View Article and Find Full Text PDFHereditas
December 2024
Facultad de Ciencias Biológicas, Departamento de Biología Celular y Genética, Universidad Autónoma de Nuevo León, San Nicolás de los Garza, Nuevo León, México.
Background: Breast cancer is the most prevalent cancer among women worldwide. Most breast cancer-related deaths result from metastasis and drug resistance. Novel therapies are imperative for targeting metastatic and drug-resistant breast cancer cells.
View Article and Find Full Text PDFStem Cell Res Ther
December 2024
Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, 250012, P.R. China.
Background: hucMSC-exosomes can be engineered to strengthen their therapeutic potential, and the present study aimed to explore whether hypoxic preconditioning can enhance the angiogenic potential of hucMSC-exosomes in an experimental model of POF.
Methods: Primary hucMSCs and ROMECs were isolated from fresh tissue samples and assessed through a series of experiments. Exosomes were isolated from hucMSCs under normoxic or hypoxic conditions (norm-Exos and hypo-Exos, respectively) and then characterized using classic experimental methods.
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!