Granulocyte Colony-Stimulating Factor and an RAR?? Specific Agonist, VTP195183, Synergize to Enhance the Mobilization of Hematopoietic Progenitor Cells

Background. Failure to mobilize adequate numbers of hematopoietic stem and progenitor cells (HSPC) is an important clinical problem. Since bone marrow (BM) neutrophils play a central role in HSPC mobilization, we hypothesized that granulocyte colony-stimulating factor (G-CSF)-mediated mobilization would be enhanced by further expanding the size of the BM granulocyte pool. Methods. We tested the potential of the retinoic acid receptor alpha (RARα) specific agonist VTP195183, and the pan-RAR agonist all-trans retinoic acid (ATRA), to enhance G-CSF-mediated mobilization of HSPC, in two mouse strains. Results. Pretreatment of mice with VTP195183 significantly increased the number of leukocytes, colony-forming cells, and early engrafting hematopoietic stem cells (HSC) mobilized in the blood in response to G-CSF. In contrast, ATRA had only a marginal effect on G-CSF-induced mobilization. HSPC mobilization synergy between VTP195183 and G-CSF occurred only when mice were preconditioned with VTP195183 prior to G-CSF. This preconditioning was shown to increase the numbers of granulocyte/macrophage progenitors in the BM. Treatment with VTP195183 and G-CSF was accompanied by enhanced levels of active neutrophil proteases in the BM extracellular fluid compared to G-CSF treatment alone. Conclusions. VTP195183 treatment increases the numbers of immature granulocyte progenitors in BM and subsequently synergizes to enhance G-CSF-mediated mobilization of HSPC. These data demonstrate a novel approach to improve G-CSF-induced mobilization by accelerating granulocyte maturation in the BM. These findings are currently being tested in a clinical trial of VTP195183 plus G-CSF for mobilization of HSPC in human patients.