학술논문
Stem cell–like reprogramming is required for leukemia-initiating activity in B-ALL
Document Type
Article
Author
Fregona, Vincent; Bayet, Manon; Bouttier, Mathieu; Largeaud, Laetitia; Hamelle, Camille; Jamrog, Laura A.; Prade, Naïs; Lagarde, Stéphanie; Hebrard, Sylvie; Luquet, Isabelle; Mansat-De Mas, Véronique; Nolla, Marie; Pasquet, Marlène; Didier, Christine; Khamlichi, Ahmed Amine; Broccardo, Cyril; Delabesse, Éric; Mancini, Stéphane J.C.; Gerby, Bastien
Source
The Journal of Experimental Medicine; January 2024, Vol. 221 Issue: 1 pe20230279-e20230279, 1p
Subject
Language
ISSN
00221007; 15409538
Abstract
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 B-ALL 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 B-ALL.