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

• Published in: Nature communications 2024-05, Vol.15 (1), p.4557-21, Article 4557
• Main Authors: Abdoul-Azize, Souleymane, Hami, Rihab, Riou, Gaetan, Derambure, Céline, Charbonnier, Camille, Vannier, Jean-Pierre, Guzman, Monica L., Schneider, Pascale, Boyer, Olivier
• Format: Article
• Language: English
• Subjects: 13/109; 13/2; 13/31; 13/89; 13/95; 14/19; 14/5; 38/35; 38/91; 42/34; 42/41; 49/1; 49/39; 631/67/1990/283/2125; 64/60; 692/308/3187; 692/4028/67/1059/2326; 96/2; 96/21; Acute lymphoblastic leukemia; Animals; Antitumor activity; Calcium ions; Cell death; Cell Line, Tumor; Cell survival; Cell Survival - drug effects; Chemokine receptors; Children; CXCR4 protein; Dexamethasone; Dexamethasone - pharmacology; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Glucocorticoids; Glucocorticoids - pharmacology; Humanities and Social Sciences; Humans; In vivo methods and tests; Internalization; Kinases; Leukemia; Lymphatic leukemia; Lymphocytes B; Mice; Mice, Inbred NOD; multidisciplinary; Pediatrics; Phospholipase; Phospholipase C; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Protein kinase C; Receptors, CXCR4 - genetics; Receptors, CXCR4 - metabolism; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - drug effects; Survival; Type C Phospholipases - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48818-9

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 Ca 2+ 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. Resistance to glucocorticoids (GC) is a major obstacle for the treatment of pediatric B-cell acute lymphoblastic leukemia (B-ALL). Here, the authors report that GC-triggered CXCR4 internalization promotes a phospholipase C (PLC)-mediated cell survival pathway, driving GC resistance in B-ALL.