Noncanonical EZH2 drives retinoic acid resistance of variant acute promyelocytic leukemias.

Autor:	Poplineau M; Epigenetic Control of Normal and Malignant Hematopoiesis, CRCM, Aix Marseille University, CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, Marseille, France.; Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.; Equipe Labellisée Ligue Nationale Contre le Cancer., Platet N; Epigenetic Control of Normal and Malignant Hematopoiesis, CRCM, Aix Marseille University, CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, Marseille, France.; Equipe Labellisée Ligue Nationale Contre le Cancer., Mazuel A; Epigenetic Control of Normal and Malignant Hematopoiesis, CRCM, Aix Marseille University, CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, Marseille, France.; Equipe Labellisée Ligue Nationale Contre le Cancer., Hérault L; Epigenetic Control of Normal and Malignant Hematopoiesis, CRCM, Aix Marseille University, CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, Marseille, France.; Equipe Labellisée Ligue Nationale Contre le Cancer.; MABioS, I2M, Aix Marseille University,CNRS UMR7373, Marseille, France., N'Guyen L; Epigenetic Control of Normal and Malignant Hematopoiesis, CRCM, Aix Marseille University, CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, Marseille, France.; Equipe Labellisée Ligue Nationale Contre le Cancer., Koide S; Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.; Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan., Nakajima-Takagi Y; Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.; Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan., Kuribayashi W; Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.; Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan., Carbuccia N; Predictive Oncology Laboratory, CRCM, Aix Marseille University, CNRS UMR7258, INSERM 1068, Institut Paoli-Calmettes, Marseille, France., Haboub L; Epigenetic Control of Normal and Malignant Hematopoiesis, CRCM, Aix Marseille University, CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, Marseille, France.; Equipe Labellisée Ligue Nationale Contre le Cancer., Vernerey J; Epigenetic Control of Normal and Malignant Hematopoiesis, CRCM, Aix Marseille University, CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, Marseille, France., Oshima M; Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.; Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan., Birnbaum D; Predictive Oncology Laboratory, CRCM, Aix Marseille University, CNRS UMR7258, INSERM 1068, Institut Paoli-Calmettes, Marseille, France., Iwama A; Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.; Division of Stem Cell and Molecular Medicine, Center for Stem Cell Biology and Regenerative Medicine, Institute of Medical Science, University of Tokyo, Tokyo, Japan., Duprez E; Epigenetic Control of Normal and Malignant Hematopoiesis, CRCM, Aix Marseille University, CNRS UMR7258, INSERM U1068, Institut Paoli-Calmettes, Marseille, France.; Equipe Labellisée Ligue Nationale Contre le Cancer.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2022 Dec 01; Vol. 140 (22), pp. 2358-2370.
DOI:	10.1182/blood.2022015668
Abstrakt:	Cancer cell heterogeneity is a major driver of therapy resistance. To characterize resistant cells and their vulnerabilities, we studied the PLZF-RARA variant of acute promyelocytic leukemia, resistant to retinoic acid (RA), using single-cell multiomics. We uncovered transcriptional and chromatin heterogeneity in leukemia cells. We identified a subset of cells resistant to RA with proliferation, DNA replication, and repair signatures that depend on a fine-tuned E2F transcriptional network targeting the epigenetic regulator enhancer of zeste homolog 2 (EZH2). Epigenomic and functional analyses validated the driver role of EZH2 in RA resistance. Targeting pan-EZH2 activities (canonical/noncanonical) was necessary to eliminate leukemia relapse-initiating cells, which underlies a dependency of resistant cells on an EZH2 noncanonical activity and the necessity to degrade EZH2 to overcome resistance. Our study provides critical insights into the mechanisms of RA resistance that allow us to eliminate treatment-resistant leukemia cells by targeting EZH2, thus highlighting a potential targeted therapy approach. Beyond RA resistance and acute promyelocytic leukemia context, our study also demonstrates the power of single-cell multiomics to identify, characterize, and clear therapy-resistant cells. (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu