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Prepublished online as a Blood First Edition Paper on May 8, 2003; DOI 10.1182/blood-2003-01-0208.
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Blood, 1 September 2003, Vol. 102, No. 5, pp. 1641-1648
HEMATOPOIESIS
Hematopoietic stimulation by a dipeptidyl peptidase inhibitor reveals a novel regulatory mechanism and therapeutic treatment for blood cell deficiencies
Barry Jones,
Sharlene Adams,
Glenn T. Miller,
Michael I. Jesson,
Takeshi Watanabe, and
Barbara P. Wallner
From Point Therapeutics Inc, Boston, MA, and the Department of Molecular
Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka,
Japan.
In hematopoiesis, cytokine levels modulate blood cell replacement,
self-renewal of stem cells, and responses to disease. Feedback pathways
regulating cytokine levels and targets for therapeutic intervention remain to
be determined. Amino boronic dipeptides are orally bioavailable inhibitors of
dipeptidyl peptidases. Here we show that the high-affinity inhibitor
Val-boro-Pro (PT-100) can stimulate the growth of hematopoietic progenitor
cells in vivo and can accelerate neutrophil and erythrocyte regeneration in
mouse models of neutropenia and acute anemia. Hematopoietic stimulation by
PT-100 correlated with increased cytokine levels in vivo. In vitro, PT-100
promoted the growth of primitive hematopoietic progenitor cells by increasing
granulocyte–colony-stimulating factor (G-CSF), interleukin-6 (IL-6), and
IL-11 production by bone marrow stromal cells. Two molecular targets of PT-100
are expressed by stromal cells— CD26/DPP-IV and the closely related
fibroblast activation protein (FAP). Because PT-100 was active in the absence
of CD26, FAP appears to be the hematopoietic target for PT-100. Interaction of
PT-100 with the catalytic site seems to be required because amino-terminal
acetylation of PT-100 abrogated enzyme inhibition and hematopoietic
stimulation. PT-100 is a therapeutic candidate for the treatment of
neutropenia and anemia. The data support increasing evidence that dipeptidyl
peptidases can regulate complex biologic systems by the proteolysis of
signaling peptides.
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