Mobilization of hematopoietic stem and progenitor cells using inhibitors of CXCR4 and VLA-4

Abstract

Successful hematopoietic stem cell transplant (HSCT) requires the infusion of a sufficient number of hematopoietic stem/progenitor cells (HSPCs) that are capable of homing to the bone marrow cavity and regenerating durable trilineage hematopoiesis in a timely fashion. Stem cells harvested from peripheral blood are the most commonly used graft source in HSCT. While granulocyte colony-stimulating factor (G-CSF) is the most frequently used agent for stem cell mobilization, the use of G-CSF alone results in suboptimal stem cell yields in a significant proportion of patients. Both the chemokine receptor CXCR4 and the integrin α4β1 (VLA-4) play important roles in the homing and retention of HSPCs within the bone marrow microenvironment. Preclinical and/or clinical studies have shown that targeted disruption of the interaction of CXCR4 or VLA-4 with their ligands results in the rapid and reversible mobilization of hematopoietic stem cells into the peripheral circulation and is synergistic when combined with G-CSF. In this review we discuss the development of small molecule CXCR4 and VLA-4 inhibitors and how they may improve the utility and convenience of peripheral blood stem cell transplantation.

Proteolytic fragments of fibronectin function as matrikines driving the chemotactic affinity of prostate cancer cells to human bone marrow mesenchymal stromal cells via the α5β1 integrin

“…This would be akin to studies demonstrating haematopoietic stem cell mobilization out of the bone marrow niche with CXCR4 and integrin a4 blockade. 20,37 These type of studies could powerfully address our proposal that the FN-Fr/FN-a5b1 interaction represents a seed-and-soil principle that defines its unique affinity for the bone marrow niche and a potential therapeutic target relevant to the lethal phenotype of the disease.…”

The role of novel and known extracellular matrix and adhesion molecules in the homeostatic and regenerative bone marrow microenvironment

“…151 Antibodies against VLA4, however, do induce mobilization. 152,153 Treatment of human HSPCs with antibodies against ITGB1 also prevented engraftment of HSPCs in mice and sheep. 154,155 ITGB1 associates with the potassium ion channel upon HSPC activation, which is essential for engraftment in the BM niche [156][157][158] and also is suggested to sustain leukemic cells in the BM-niche.…”

New agents in HSC mobilization

“…However, similar studies using the orally bioavailable dual α 4 β 1 /α 4 β 7 antagonist firategrast (SB-683699) (Fig. 2), which is currently in clinical development for treatment of MS, will be tested in due course for efficacy in HSC mobilization in murine models [85].…”