Constitutive mobilization of CD34+ cells into the peripheral blood in idiopathic myelofibrosis may be due to the action of a number of proteases.
Idiopathic myelofibrosis (IM) is characterized by increased numbers of CD34(+) cells in the peripheral blood (PB). We explored the possible mechanisms underlying this abnormal trafficking of CD34(+) cells. Plasma levels of neutrophil elastase (NE), total and active matrix metalloproteinase 9 (MMP-9), and soluble vascular cell adhesion molecule-1 (sVCAM-1) were dramatically increased in IM. The absolute number of CD34(+) cells in the PB was correlated with the levels of sVCAM-1. Marked elevations of the levels of NE but not total and active MMP-9 as well as MMP-2 were detected in media conditioned by IM mononuclear cells (MNCs) as compared with that of healthy volunteers. IM MNC-conditioned media, however, was shown by zymographic analysis to contain increased gelatinolytic activity corresponding to the molecular weight of MMP-9. IM MNC-conditioned media also exhibited a greater ability to cleave VCAM-1 and c-kit in vitro, consistent with the biologic actions of NE. In addition, the increased ability of IM PB CD34(+) cells to migrate through a reconstituted basement membrane was diminished by several inhibitors of MMP-9 activity, indicating that these cells express increased levels of this MMP. These data indicate that a proteolytic environment exists in IM which might result in the sustained mobilization of CD34(+) cells.
Xu
Mingjiang
M
Section of Hematology/Oncology, University of Illinois at Chicago Cancer Center, University of Illinois College of Medicine, IL, USA.
Bruno
Edward
E
Chao
Joseph
J
Huang
Stephen
S
Finazzi
Guido
G
Fruchtman
Steven M
SM
Popat
Uday
U
Prchal
Josef T
JT
Barosi
Giovanni
G
Hoffman
Ronald
R
D018952:Antigens, CD34; D001773:Blood Cells / Q000473:pathology; D002465:Cell Movement; D017077:Culture Media, Conditioned / Q000737:chemistry; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D019272:Leukocyte Elastase / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism*; D055728:Primary Myelofibrosis / Q000097:blood / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D018952:Antigens, CD34; D017077:Culture Media, Conditioned; D009363:Neoplasm Proteins; D019010:Vascular Cell Adhesion Molecule-1; D010447:Peptide Hydrolases; D019272:Leukocyte Elastase; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9