High caspase 3 and vulnerability to dual BCL2 family inhibition define ETO2::GLIS2 pediatric leukemia.

Autor: Aid Z; INSERM U1170, Gustave Roussy Cancer Campus, Université Paris Saclay, PEDIAC program, 94800, Villejuif, France.; Equipe labellisée Ligue Nationale Contre le Cancer, 75013, Paris, France., Robert E; INSERM U1170, Gustave Roussy Cancer Campus, Université Paris Saclay, PEDIAC program, 94800, Villejuif, France.; Equipe labellisée Ligue Nationale Contre le Cancer, 75013, Paris, France., Lopez CK; INSERM U1170, Gustave Roussy Cancer Campus, Université Paris Saclay, PEDIAC program, 94800, Villejuif, France. cal78@cam.ac.uk.; Equipe labellisée Ligue Nationale Contre le Cancer, 75013, Paris, France. cal78@cam.ac.uk.; Wellcome Trust-MRC Cambridge Stem Cell Institute, Cambridge, UK. cal78@cam.ac.uk.; Department of Haematology, University of Cambridge, Cambridge, UK. cal78@cam.ac.uk., Bourgoin M; Team 'Myeloid Malignancies and Multiple Myeloma', Université Côte d'Azur, INSERM U1065/C3M, 06204, Nice, France., Boudia F; INSERM U1170, Gustave Roussy Cancer Campus, Université Paris Saclay, PEDIAC program, 94800, Villejuif, France.; Equipe labellisée Ligue Nationale Contre le Cancer, 75013, Paris, France., Le Mene M; INSERM U1170, Gustave Roussy Cancer Campus, Université Paris Saclay, PEDIAC program, 94800, Villejuif, France.; Equipe labellisée Ligue Nationale Contre le Cancer, 75013, Paris, France., Riviere J; INSERM U1170, Gustave Roussy Cancer Campus, Université Paris Saclay, PEDIAC program, 94800, Villejuif, France.; Equipe labellisée Ligue Nationale Contre le Cancer, 75013, Paris, France., Baille M; INSERM U1170, Gustave Roussy Cancer Campus, Université Paris Saclay, PEDIAC program, 94800, Villejuif, France.; Equipe labellisée Ligue Nationale Contre le Cancer, 75013, Paris, France., Benbarche S; INSERM U1170, Gustave Roussy Cancer Campus, Université Paris Saclay, PEDIAC program, 94800, Villejuif, France., Renou L; Unité de Recherche (UMR)-E008 Stabilité Génétique, Cellules Souches et Radiations, Team Niche and Cancer in Hematopoiesis, Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Université de Paris-Université Paris-Saclay, Fontenay-aux-Roses, 92260, France., Fagnan A; INSERM U1170, Gustave Roussy Cancer Campus, Université Paris Saclay, PEDIAC program, 94800, Villejuif, France.; Equipe labellisée Ligue Nationale Contre le Cancer, 75013, Paris, France., Thirant C; INSERM U1170, Gustave Roussy Cancer Campus, Université Paris Saclay, PEDIAC program, 94800, Villejuif, France.; Equipe labellisée Ligue Nationale Contre le Cancer, 75013, Paris, France., Federici L; INSERM U1170, Gustave Roussy Cancer Campus, Université Paris Saclay, PEDIAC program, 94800, Villejuif, France.; Equipe labellisée Ligue Nationale Contre le Cancer, 75013, Paris, France., Touchard L; Unité Mixte de Service - Analyse Moléculaire Modélisation et Imagerie de la maladie Cancéreuse (UMS AMMICA), Gustave Roussy Cancer Campus, 94800, Villejuif, France., Lecluse Y; Unité Mixte de Service - Analyse Moléculaire Modélisation et Imagerie de la maladie Cancéreuse (UMS AMMICA), Gustave Roussy Cancer Campus, 94800, Villejuif, France., Jetten A; Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA., Geoerger B; Gustave Roussy Cancer Campus, Pediatric and Adolescent Oncology Department, INSERM U1015, Université Paris Saclay, 94800, Villejuif, France., Lapillonne H; Pediatric Hematology and Oncology Department, Armand Trousseau Hospital, AP-HP, Sorbonne University, UMRS_938, CONECT-AML, 75012, Paris, France., Solary E; INSERM U1287, Gustave Roussy Cancer Campus, 94800, Villejuif, France., Gaudry M; INSERM U1170, Gustave Roussy Cancer Campus, Université Paris Saclay, PEDIAC program, 94800, Villejuif, France.; Equipe labellisée Ligue Nationale Contre le Cancer, 75013, Paris, France., Meshinchi S; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Pflumio F; Unité de Recherche (UMR)-E008 Stabilité Génétique, Cellules Souches et Radiations, Team Niche and Cancer in Hematopoiesis, Commissariat à l'Energie Atomique et aux Energies Alternatives (CEA), Université de Paris-Université Paris-Saclay, Fontenay-aux-Roses, 92260, France.; OPALE Carnot Institute, The Organization for Partnerships in Leukemia, 75010, Paris, France., Auberger P; Team 'Myeloid Malignancies and Multiple Myeloma', Université Côte d'Azur, INSERM U1065/C3M, 06204, Nice, France.; OPALE Carnot Institute, The Organization for Partnerships in Leukemia, 75010, Paris, France., Lobry C; INSERM U1170, Gustave Roussy Cancer Campus, Université Paris Saclay, PEDIAC program, 94800, Villejuif, France.; INSERM U944, CNRS UMR7212, Institut de Recherche Saint Louis and Université de Paris, 75010, Paris, France., Petit A; Gustave Roussy Cancer Campus, Pediatric and Adolescent Oncology Department, INSERM U1015, Université Paris Saclay, 94800, Villejuif, France.; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Jacquel A; Team 'Myeloid Malignancies and Multiple Myeloma', Université Côte d'Azur, INSERM U1065/C3M, 06204, Nice, France. Arnaud.Jacquel@unice.fr., Mercher T; INSERM U1170, Gustave Roussy Cancer Campus, Université Paris Saclay, PEDIAC program, 94800, Villejuif, France. thomas.mercher@inserm.fr.; Equipe labellisée Ligue Nationale Contre le Cancer, 75013, Paris, France. thomas.mercher@inserm.fr.; OPALE Carnot Institute, The Organization for Partnerships in Leukemia, 75010, Paris, France. thomas.mercher@inserm.fr.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2023 Mar; Vol. 37 (3), pp. 571-579. Date of Electronic Publication: 2022 Dec 30.
DOI: 10.1038/s41375-022-01800-0
Abstrakt: Pediatric acute myeloid leukemia expressing the ETO2::GLIS2 fusion oncogene is associated with dismal prognosis. Previous studies have shown that ETO2::GLIS2 can efficiently induce leukemia development associated with strong transcriptional changes but those amenable to pharmacological targeting remained to be identified. By studying an inducible ETO2::GLIS2 cellular model, we uncovered that de novo ETO2::GLIS2 expression in human cells led to increased CASP3 transcription, CASP3 activation, and cell death. Patient-derived ETO2::GLIS2 + leukemic cells expressed both high CASP3 and high BCL2. While BCL2 inhibition partly inhibited ETO2::GLIS2 + leukemic cell proliferation, BH3 profiling revealed that it also sensitized these cells to MCL1 inhibition indicating a functional redundancy between BCL2 and MCL1. We further show that combined inhibition of BCL2 and MCL1 is mandatory to abrogate disease progression using in vivo patient-derived xenograft models. These data reveal that a transcriptional consequence of ETO2::GLIS2 expression includes a positive regulation of the pro-apoptotic CASP3 and associates with a vulnerability to combined targeting of two BCL2 family members providing a novel therapeutic perspective for this aggressive pediatric AML subgroup.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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