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.
Stem cell–like reprogramming is required for leukemia-initiating activity in B-ALL
Disclosures: The authors declare no competing interests exist.
- Award Id(s): INCa-2020-096
- Award Id(s): ANR-18-CE13-0002-01
- Award Id(s): PJA-20181207977
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, Ahmed Amine Khamlichi, Cyril Broccardo, Éric Delabesse, Stéphane J.C. Mancini, Bastien Gerby; Stem cell–like reprogramming is required for leukemia-initiating activity in B-ALL. J Exp Med 1 January 2024; 221 (1): e20230279. doi: https://doi.org/10.1084/jem.20230279
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