Genetic deletion of JAM-C in pre-leukemic cells rewires leukemic stem cell gene expression program in AML - Anthropologie Bio-culturelle, Droit, Éthique, Santé - UMR 7268 ADES
Article Dans Une Revue Blood Advances Année : 2024

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

Samuel Granjeaud
Christophe Zemmour
Jean-François Spinella
Josée Hébert
Norbert Vey
Juerg Schwaller
Cyril Fauriat
  • Fonction : Auteur
  • PersonId : 1031830
Michel Aurrand-Lions

Résumé

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, our understanding of the relationships between LSC and pre-leukemic cells is still incomplete. In particular, it is not known whether "niche-anchoring" of pre-leukemic cell affects disease evolution. To address this issue, we conditionally inactivated the adhesion molecule JAM-C expressed by haematopoietic stem cells (HSC) and LSC in an inducible 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 HSC isolated from diseased mice revealed that genes upregulated in Jam3-deficient animals belonged to Activation Protein-1 (AP-1) and TNF-/NFB pathways. Human orthologs of dysregulated genes allowed to identify a score based on AP-1/TNF-a gene expression that was distinct and complementary from LSC-17 score. Sub-stratification of AML patients with LSC-17 and AP-1/TNF-genes signature defined four groups with median survival ranging from below one year to a median 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- gene signature as a proxy of LSC anchoring in specific bone marrow niches which improves the prognosis value of the LSC-17 score. NCT02320656

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Cancer
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inserm-04659813 , version 1 (10-12-2024)

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Julien M.P. Grenier, Céline Testut, Matthieu Bal, Florence Bardin, Maria de Grandis, et al.. Genetic deletion of JAM-C in pre-leukemic cells rewires leukemic stem cell gene expression program in AML. Blood Advances, 2024, 8 (17), pp.4662-4678. ⟨10.1182/bloodadvances.2023011747⟩. ⟨inserm-04659813⟩

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