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 plerixaf...

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Bibliographic Details
Published in:Blood 2009-08, Vol.114 (7), p.1340-1343
Main Authors: Ramirez, Pablo, Rettig, Michael P., Uy, Geoffrey L., Deych, Elena, Holt, Matthew S., Ritchey, Julie K., DiPersio, John F.
Format: Article
Language:English
Subjects:
Animals
Anti-HIV Agents - pharmacology
Biological and medical sciences
Chemokine CXCL12 - metabolism
Granulocyte Colony-Stimulating Factor - metabolism
Granulocyte Colony-Stimulating Factor - pharmacology
Hematologic and hematopoietic diseases
Hematopoiesis and Stem Cells
Hematopoietic Stem Cell Mobilization - methods
Hematopoietic Stem Cells - cytology
Hematopoietic Stem Cells - metabolism
Heterocyclic Compounds - pharmacology
Integrin alpha4beta1 - antagonists & inhibitors
Integrin alpha4beta1 - metabolism
Medical sciences
Mice
Oligopeptides - pharmacology
Phenylurea Compounds - pharmacology
Receptors, CXCR4 - metabolism
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Summary: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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2008-10-184721