Genetic deletion of JAM-C in preleukemic cells rewires leukemic stem cell gene expression program in AML.

Autor:	Grenier JMP; Aix Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Equipe Labellisée Ligue 2020, Marseille, France.; UMR 7268, Aix-Marseille Université, EFS, CNRS, GENGLOBE, Marseille, France., Testut C; Aix Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Equipe Labellisée Ligue 2020, Marseille, France., Bal M; Aix Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Equipe Labellisée Ligue 2020, Marseille, France.; Département de la Recherche Clinique et de l'Innovation, Institut Paoli-Calmettes, Marseille, France., Bardin F; Aix Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Equipe Labellisée Ligue 2020, Marseille, France., De Grandis M; Aix-Marseille University, CNRS, EFS, ADES, Biologie des Groupes Sanguins, Marseille, France.; UMR 7268, Aix-Marseille Université, EFS, CNRS, GENGLOBE, Marseille, France., Gelsi-Boyer V; Aix Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Equipe Labellisée Ligue 2020, Marseille, France., Vernerey J; Aix Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Equipe Labellisée Ligue 2020, Marseille, France., Delahaye M; Aix Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Equipe Labellisée Ligue 2020, Marseille, France., Granjeaud S; Aix Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Equipe Labellisée Ligue 2020, Marseille, France., Zemmour C; Département de la Recherche Clinique et de l'Innovation, Institut Paoli-Calmettes, Marseille, France., Spinella JF; Laboratory of Molecular Genetics of Stem Cells, Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada., Chavakis T; Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany., Mancini SJC; UMR 1236, University of Rennes, INSERM, Etablissement Français du Sang Bretagne, Rennes, France., Boher JM; Département de la Recherche Clinique et de l'Innovation, Institut Paoli-Calmettes, Marseille, France., Hébert J; Division of Hematology-Oncology, Department of Medicine, Maisonneuve-Rosemont Hospital, Université de Montréal, Montreal, QC, Canada., Sauvageau G; Laboratory of Molecular Genetics of Stem Cells, Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada., Vey N; Aix Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Equipe Labellisée Ligue 2020, Marseille, France., Schwaller J; Department of Biomedicine, University Children's Hospital, University of Basel, Basel, Switzerland., Hospital MA; Département d'Hématologie, Institut Paoli-Calmettes, Marseille, France., Fauriat C; Aix Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Equipe Labellisée Ligue 2020, Marseille, France., Aurrand-Lions M; Aix Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Equipe Labellisée Ligue 2020, Marseille, France.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2024 Sep 10; Vol. 8 (17), pp. 4662-4678.
DOI:	10.1182/bloodadvances.2023011747
Abstrakt:	Abstract: The leukemic stem cell (LSC) score LSC-17 based on a stemness-related gene expression signature is an indicator of poor disease outcome in acute myeloid leukemia (AML). However, it is not known whether "niche anchoring" of LSC affects disease evolution. To address this issue, we conditionally inactivated the adhesion molecule JAM-C (Junctional Adhesion Molecule-C) expressed by hematopoietic stem cells (HSCs) and LSCs in an inducible mixed-lineage leukemia (iMLL)-AF9-driven AML mouse model. Deletion of Jam3 (encoding JAM-C) before induction of the leukemia-initiating iMLL-AF9 fusion resulted in a shift from long-term to short-term HSC expansion, without affecting disease initiation and progression. In vitro experiments showed that JAM-C controlled leukemic cell nesting irrespective of the bone marrow stromal cells used. RNA sequencing performed on leukemic HSCs isolated from diseased mice revealed that genes upregulated in Jam3-deficient animals belonged to activation protein-1 (AP-1) and tumor necrosis factor α (TNF-α)/NF-κB pathways. Human orthologs of dysregulated genes allowed to identify a score that was distinct from, and complementary to, the LSC-17 score. Substratification of patients with AML using LSC-17 and AP-1/TNF-α genes signature defined 4 groups with median survival ranging from <1 year to a median of "not reached" after 8 years. Finally, coculture experiments showed that AP-1 activation in leukemic cells was dependent on the nature of stromal cells. Altogether, our results identify the AP-1/TNF-α gene signature as a proxy of LSC anchoring in bone marrow niches, which improves the prognostic value of the LSC-17 score. This trial was registered at www.ClinicalTrials.gov as #NCT02320656. (© 2024 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
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