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Blood, 1 June 2005, Vol. 105, No. 11, pp. 4508-4515.
Prepublished online as a Blood First Edition Paper on February 10, 2005; DOI 10.1182/blood-2004-08-3238.
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Submitted August 23, 2004
Accepted January 29, 2005
The constitutive mobilization of CD34+ cells into the peripheral blood in idiopathic myelofibrosis may be due to the action of a number of proteases
Mingjiang Xu, Edward Bruno, Joseph Chao, Stephen Huang, Guido Finazzi, Steven M Fruchtman, Uday Popat, Josef T Prchal, Giovanni Barosi, and Ronald Hoffman*
Section of Hematology/Oncology, University of Illinois at Chicago Cancer Center, University of Illinois College of Medicine, Chicago, IL, USA
Department of Hematology, Ospedali Riuniti, Bergamo, IL, Italy
Mount Sinai School of Medicine, New York, NY, USA
Baylor College of Medicine, Houston, TX, USA
The Instituto di Ricoveroe Cura a Corattere Scientifico (IRCCS) Policlinico S. Matteo, Pavia, Italy
* Corresponding author; email: ronhoff{at}uic.edu.
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 (MMP)-9 and soluble VCAM-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 (MNC) as compared to that of normal 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 biological 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.

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