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

Author

Listed:
  • 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
    Department of Pediatric Immuno-Hemato-Oncology)

  • Olivier Boyer

    (UMR 1234
    Department of Immunology and Biotherapy)

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.

Suggested Citation

  • Souleymane Abdoul-Azize & Rihab Hami & Gaetan Riou & Céline Derambure & Camille Charbonnier & Jean-Pierre Vannier & Monica L. Guzman & Pascale Schneider & Olivier Boyer, 2024. "Glucocorticoids paradoxically promote steroid resistance in B cell acute lymphoblastic leukemia through CXCR4/PLC signaling," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48818-9
    DOI: 10.1038/s41467-024-48818-9
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