Glucocorticoids-triggered CXCR4 signaling activates the PLC signalosome and promotes tumor resistance in B cell acute lymphoblastic leukemia

Approximately 20-25% of patients with acute lymphoblastic leukemia (ALL) relapse after initial chemotherapy and become resistant to glucocorticoids (GC). Although GC signaling act on well-defined transcriptional responses via GC receptors (GCR), there is emerging evidence that GC also mediate transcription-independent signaling events that appear to be very rapid. We previously established that rapid calcium-mediated cell survival signals, triggered by GC stimulation, are involved in the resistance to GC anti-leukemic effects. Furthermore, we demonstrated that chelating intracellular calcium with Bapta-AM or inhibiting downstream ERK1/2 signaling with PD98059 overcame GC resistance in ALL samples. Here, we investigate the potential role of PLC in GC resistance. We identified that Dexamethasone (Dex) induced cytosolic calcium release via a mechanism involving the cell surface receptor of CXCL12 (CXCR4) internalization and subsequent activation of PLC signalosome. We found that PLC inhibition was able to induce cell death in GC-resistant B-ALL cells by compromising the expression of genes in several metabolic pathways including cell cycle checkpoints, glycolysis and mitochondrial function. These results establish a role for nongenomic signaling in ALL resistance to GC and support identifying novel therapeutics targeting Ca2+ signaling to restore GC sensitivity. We generated GC-resistant cell line by in vitro long-term dexamethasone treatment. GC resistant Nalm-6 cells were treated with or without PLC inhibitor, U73122 (NU), or DMSO (NC) for 16 hours. Samples were then hybrized to RNA sequencing in duplicate.