Bortezomib enhances G-CSF-induced hematopoietic stem cell mobilization by decreasing CXCL12 levels and increasing vascular permeability

Abstract

Bortezomib (BTZ) is known to enhance the mobilization of hematopoietic stem and progenitor cells (HSPCs) induced by granulocyte colony-stimulating factor (G-CSF). However, the most effective time at which to administer BTZ to produce this enhancing effect remains debatable, and the precise mechanism underlying the effect of BTZ is poorly understood. We addressed these questions in this article by performing animal experiments. First, in agreement with previous studies, BTZ administration 12 hours before blood collection was most effective for HSPC mobilization; in contrast, BTZ administration 3 days before blood collection negatively affected HSPC harvesting. Next, in terms of the mechanism of action, G-CSF, but not BTZ, downregulated the expression of very late antigen-4 on HSPCs and vascular cell adhesion molecule-1 on bone marrow (BM) stromal cells; however, intriguingly, both G-CSF and BTZ downregulated CXCL12 chemokine expression in BM. Notably, BTZ treatment also increased BM vascular permeability. These results suggest that the pro-mobilization effect of BTZ could involve the dissociation of HSPCs from BM stromal cells triggered by G-CSF, vascular hyperpermeability elicited by BTZ, and downregulation of CXCL12 concomitantly induced by G-CSF and BTZ.