Th6 - A CXCR4/PLC-mediated Cell Survival Pathway is Involved in Steroid Resistance of B-acute Lymphoblastic Leukemia

The initial response to glucocorticoids (GC) is an important predictor of outcome in B acute lymphoblastic leukemia (B-ALL). We recently showed that intracellular Ca²⁺ or downstream ERK signaling mediates dexamethasone (Dex) resistance in B-ALL cells. We now hypothesize that PLC-mediated Ca²⁺ signaling contributes to Dex resistance and show herein that GC paradoxically promote a CXCR4/PLC-mediated cell survival pathway in B lymphoblasts.

Dex provoked a decrease in CXCR4 membrane expression via internalization, resulting in activation of PLC dependent-Ca²⁺ signaling. The PLC inhibitor U73122, the CXCR4 antagonist AMD310 and CXCR4 gene silencing decreased Dex-induced calcium signaling. Exposing B-ALL cells to the CXCR4 ligand SDF-1 induced rapid increase in [Ca²⁺]i. SDF-1 potentiated GC resistance in B lymphoblasts. This resistance could be overcome by AMD3100. Also, U73122 and CXCR4 gene silencing allowed overcoming GC resistance, leading to a significant increase in Dex-induced reactive oxygen species production, cytochrome c release, caspase-3 activation and eventually apoptosis. Treatment with Dex and AMD3465 also significantly delayed Nalm6 leukemia development in NSG mice. Bioinformatic analysis of B-ALL datasets revealed that CXCR4 expression is higher in GC-resistant as compared to GC-sensitive ALL patients, further supporting a role of CXCR4 in sensitivity to GC. In this line, patients with high expression of CXCR4 had a poorer clinical outcome than low-expressors.

Taken together, these data indicate that GC paradoxically induce their own resistance in B lymphoblasts by stimulating a CXCR4-mediated pro-survival pathway through the activation of PLC.

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