BIO5192, a small molecule inhibitor of VLA-4, mobilizes hematopoietic stem and progenitor cells.
Here we show that interruption of the VCAM-1/VLA-4 axis with a small molecule inhibitor of VLA-4, BIO5192, results in a 30-fold increase in mobilization of murine hematopoietic stem and progenitors (HSPCs) over basal levels. An additive affect on HSPC mobilization (3-fold) was observed when plerixafor (AMD3100), a small molecule inhibitor of the CXCR-4/SDF-1 axis, was combined with BIO5192. Furthermore, the combination of granulocyte colony-stimulating factor (G-CSF), BIO5192, and plerixafor enhanced mobilization by 17-fold compared with G-CSF alone. HSPCs mobilized by BIO5192 or the combination of BIO5192 and plerixafor mobilized long-term repopulating cells, which successfully engraft and expand in a multilineage fashion in secondary transplantation recipients. Splenectomy resulted in a dramatic enhancement of G-CSF-induced mobilization while decreasing both plerixafor- and BIO5192-induced mobilization of HSPCs. These data provide evidence for the utility of small molecule inhibitors of VLA-4 either alone or in combination with G-CSF or AMD3100 for mobilization of hematopoietic stem and progenitor cells.
Ramirez
Pablo
P
Divisions of Oncology, Washington University School of Medicine, St Louis, MO 63110, USA.
Rettig
Michael P
MP
Uy
Geoffrey L
GL
Deych
Elena
E
Holt
Matthew S
MS
Ritchey
Julie K
JK
DiPersio
John F
JF
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology; D001596:Benzylamines; D054377:Chemokine CXCL12 / Q000378:metabolism; D000080027:Cyclams; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000494:pharmacology; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000378:metabolism
C475231:2-((1-(3,5-dichlorobenzenesulfonyl)pyrrolidine-2-carbonyl)amino)-4-(4-methyl-2-(methyl-(2-(4-(3-o-tolylureido)phenyl)acetyl)amino)pentanoylamino)butyric acid; D019380:Anti-HIV Agents; D001596:Benzylamines; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D039041:Integrin alpha4beta1; D009842:Oligopeptides; D010671:Phenylurea Compounds; D019718:Receptors, CXCR4; D016179:Granulocyte Colony-Stimulating Factor; C088327:plerixafor