Effects of pharmacological and genetic disruption of CXCR4 chemokine receptor function in B‐cell acute lymphoblastic leukaemia

Summary B cell acute lymphoblastic leukaemia (B‐ ALL ) cells express high levels of CXCR 4 chemokine receptors for homing and retention within the marrow microenvironment. Bone marrow stromal cells ( BMSC ) secrete CXCL 12, the ligand for CXCR 4, and protect B‐ ALL cells from cytotoxic drugs. Therefore, the therapeutic use of CXCR 4 antagonists has been proposed to disrupt cross talk between B‐ ALL cells and the protective stroma. Because CXCR 4 antagonists can have activating agonistic function, we compared the genetic and pharmacological deletion of CXCR 4 in B‐ ALL cells, using CRISPR ‐Cas9 gene editing and CXCR 4 antagonists that are in clinical use (plerixafor, BKT 140). Both genetic and pharmacological CXCR 4 inhibition significantly reduced B‐ ALL cell migration to CXCL 12 gradients and beneath BMSC , and restored drug sensitivity to dexamethasone, vincristine and cyclophosphamide. NOD / SCID / IL ‐2rγnull mice injected with CXCR 4 gene‐deleted B‐ ALL cells had significant delay in disease progression and superior survival when compared to control mice injected with CXCR 4 wild‐type B‐ ALL cells. These findings indicate that anti‐leukaemia activity of CXCR 4 antagonists is primarily due to CXCR 4 inhibition, rather than agonistic activity, and corroborate that CXCR 4 is an important target to overcome stroma‐mediated drug resistance in B‐ ALL .