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

Author:

Grenier Julien M. P.12,Testut Céline1,Bal Matthieu13,Bardin Florence1,De Grandis Maria42ORCID,Gelsi-Boyer Véronique1,Vernerey Julien1,Delahaye Marjorie1,Granjeaud Samuel1ORCID,Zemmour Christophe3ORCID,Spinella Jean-François5ORCID,Chavakis Triantafyllos6,Mancini Stéphane J. C.7,Boher Jean-Marie3,Hébert Josée8ORCID,Sauvageau Guy5,Vey Norbert1ORCID,Schwaller Jürg9ORCID,Hospital Marie-Anne10,Fauriat Cyril1ORCID,Aurrand-Lions Michel1ORCID

Affiliation:

1. 1Aix Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Equipe Labellisée Ligue 2020, Marseille, France

2. 4UMR 7268, Aix-Marseille Université, EFS, CNRS, GENGLOBE, Marseille, France

3. 2Département de la Recherche Clinique et de l’Innovation, Institut Paoli-Calmettes, Marseille, France

4. 3Aix-Marseille University, CNRS, EFS, ADES, Biologie des Groupes Sanguins, Marseille, France

5. 5Laboratory of Molecular Genetics of Stem Cells, Institute for Research in Immunology and Cancer, University of Montreal, Montreal, QC, Canada

6. 6Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany

7. 7UMR 1236, University of Rennes, INSERM, Etablissement Français du Sang Bretagne, Rennes, France

8. 8Division of Hematology-Oncology, Department of Medicine, Maisonneuve-Rosemont Hospital, Université de Montréal, Montreal, QC, Canada

9. 9Department of Biomedicine, University Children’s Hospital, University of Basel, Basel, Switzerland

10. 10Département d'Hématologie, Institut Paoli-Calmettes, Marseille, France

Abstract

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.

Publisher

American Society of Hematology

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