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Article Dans Une Revue Journal of Experimental Medicine Année : 2023

Stem cell–like reprogramming is required for leukemia-initiating activity in B-ALL

Une reprogrammation de type cellule souche est nécessaire pour l’activité initiatrice de la leucémie dans B-ALL

Vincent Fregona
Manon Bayet
Mathieu Bouttier
Laetitia Largeaud
Camille Hamelle
Laura A Jamrog
Naïs Prade
Stéphanie Lagarde
Sylvie Hebrard
Isabelle Luquet
Véronique Mansat-de Mas
Marie Nolla
Marlène Pasquet
Christine Didier
Cyril Broccardo
Éric Delabesse
Stéphane J C Mancini

Résumé

B cell acute lymphoblastic leukemia (B-ALL) is a multistep disease characterized by the hierarchical acquisition of genetic alterations. However, the question of how a primary oncogene reprograms stem cell-like properties in committed B cells and leads to a preneoplastic population remains unclear. Here, we used the PAX5::ELN oncogenic model to demonstrate a causal link between the differentiation blockade, the self-renewal, and the emergence of preleukemic stem cells (pre-LSCs). We show that PAX5::ELN disrupts the differentiation of preleukemic cells by enforcing the IL7r/JAK-STAT pathway. This disruption is associated with the induction of rare and quiescent pre-LSCs that sustain the leukemia-initiating activity, as assessed using the H2B-GFP model. Integration of transcriptomic and chromatin accessibility data reveals that those quiescent pre-LSCs lose B cell identity and reactivate an immature molecular program, reminiscent of human BALL chemo-resistant cells. Finally, our transcriptional regulatory network reveals the transcription factor EGR1 as a strong candidate to control quiescence/ resistance of PAX5::ELN pre-LSCs as well as of blasts from human BALL .
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Dates et versions

hal-04283055 , version 1 (13-11-2023)

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Vincent Fregona, Manon Bayet, Mathieu Bouttier, Laetitia Largeaud, Camille Hamelle, et al.. Stem cell–like reprogramming is required for leukemia-initiating activity in B-ALL. Journal of Experimental Medicine, 2023, 221 (1), ⟨10.1084/jem.20230279⟩. ⟨hal-04283055⟩
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