Glucocorticoids paradoxically promote steroid resistance in B cell acute lymphoblastic leukemia through CXCR4/PLC signaling

Souleymane Abdoul-Azize (), Rihab Hami, Gaetan Riou, Céline Derambure, Camille Charbonnier, Jean-Pierre Vannier, Monica L. Guzman, Pascale Schneider and Olivier Boyer
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Souleymane Abdoul-Azize: UMR 1234
Rihab Hami: UMR 1101
Gaetan Riou: UMR 1234
Céline Derambure: UMR 1245
Camille Charbonnier: UMR 1245
Jean-Pierre Vannier: UMR 1234
Monica L. Guzman: Weill Cornell Medicine
Pascale Schneider: UMR 1234
Olivier Boyer: UMR 1234

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract Glucocorticoid (GC) resistance in childhood relapsed B-cell acute lymphoblastic leukemia (B-ALL) represents an important challenge. Despite decades of clinical use, the mechanisms underlying resistance remain poorly understood. Here, we report that in B-ALL, GC paradoxically induce their own resistance by activating a phospholipase C (PLC)-mediated cell survival pathway through the chemokine receptor, CXCR4. We identify PLC as aberrantly activated in GC-resistant B-ALL and its inhibition is able to induce cell death by compromising several transcriptional programs. Mechanistically, dexamethasone (Dex) provokes CXCR4 signaling, resulting in the activation of PLC-dependent Ca2+ and protein kinase C signaling pathways, which curtail anticancer activity. Treatment with a CXCR4 antagonist or a PLC inhibitor improves survival of Dex-treated NSG mice in vivo. CXCR4/PLC axis inhibition significantly reverses Dex resistance in B-ALL cell lines (in vitro and in vivo) and cells from Dex resistant ALL patients. Our study identifies how activation of the PLC signalosome in B-ALL by Dex limits the upfront efficacy of this chemotherapeutic agent.

Date: 2024
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DOI: 10.1038/s41467-024-48818-9

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