Effects of pharmacological and genetic disruption of CXCR4 chemokine receptor function in B‐cell acute lymphoblastic leukaemia. (12th April 2016)

• Record Type: Journal Article
• Authors: Randhawa, Shubhchintan; Cho, Byung S.; Ghosh, Dipanjan; Sivina, Mariela; Koehrer, Stefan; Müschen, Markus; Peled, Amnon; Davis, Richard E.; Konopleva, Marina; Burger, Jan A.
• Is Part Of: British journal of haematology. Volume 174:Number 3(2016)
• Page Start: 425
• Page End: 436
• Publication Date: 2016-04-12
• Subjects: B‐acute lymphoblastic leukaemia -- CXCR4 -- CXCL12 -- CRISPR‐Cas9 -- bone marrow microenvironment; Hematology -- Periodicals; Blood -- Diseases -- Periodicals; 616.15
• DOI: 10.1111/bjh.14075
• Languages: English
• ISSNs: 0007-1048

Abstract

Summary: B cell acute lymphoblastic leukaemia (B‐ALL) cells express high levels of CXCR4 chemokine receptors for homing and retention within the marrow microenvironment. Bone marrow stromal cells (BMSC) secrete CXCL12, the ligand for CXCR4, and protect B‐ALL cells from cytotoxic drugs. Therefore, the therapeutic use of CXCR4 antagonists has been proposed to disrupt cross talk between B‐ALL cells and the protective stroma. Because CXCR4 antagonists can have activating agonistic function, we compared the genetic and pharmacological deletion of CXCR4 in B‐ALL cells, using CRISPR‐Cas9 gene editing and CXCR4 antagonists that are in clinical use (plerixafor, BKT140). Both genetic and pharmacological CXCR4 inhibition significantly reduced B‐ALL cell migration to CXCL12 gradients and beneath BMSC, and restored drug sensitivity to dexamethasone, vincristine and cyclophosphamide. NOD/SCID/IL‐2rγnull mice injected with CXCR4 gene‐deleted B‐ALL cells had significant delay in disease progression and superior survival when compared to control mice injected with CXCR4 wild‐type B‐ALL cells. These findings indicate that anti‐leukaemia activity of CXCR4 antagonists is primarily due to CXCR4 inhibition, rather than agonistic activity, and corroborate that CXCR4 is an important target to overcome stroma‐mediated drug resistance in B‐ALL.