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Blood, 1 August 2007, Vol. 110, No. 3, pp. 986-993.
Prepublished online as a Blood First Edition Paper on May 1, 2007; DOI 10.1182/blood-2006-12-064626.
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Submitted December 21, 2006
Accepted April 22, 2007
Pivotal contributions of megakaryocytes to the biology of idiopathic myelofibrosis
Stefan O. Ciurea, Delwin Merchant, Nadim Mahmud, Takefumi Ishii, Yan Zhao, Wenyang Hu, Edward Bruno, Giovanni Barosi, Mingjiang Xu, and Ronald Hoffman*
Division of Hematology Oncology, Department of Medicine, University of Illinois College of Medicine, Chicago, IL, United States
Division of Hematology, IRCCS Policlinico S. Matteo, Pavia, Italy
Myeloproliferative Diseases Research Consortium
* Corresponding author; email: ronhoff{at}uic.edu.
In order to investigate the biological processes underlying and resulting from the megakaryocytic hyperplasia which characterizes idiopathic myelofibrosis (IMF), peripheral blood CD34+ cells isolated from patients with IMF, polycythemia vera (PV) and G-CSF mobilized normal volunteers were cultured in the presence of stem cell factor and thrombopoietin. IMF CD34+ cells generated 24 fold greater numbers of megakaryocytes (MKs) than normal CD34+ cells. IMF MKs were also shown to have a delayed pattern of apoptosis and to over-express the anti-apoptotic protein bcl-xL. MK hyperplasia in IMF is, therefore, likely a consequence of both the increased ability of IMF progenitor cells to generate MKs and a decreased rate of MK apoptosis. Media conditioned (CM) by CD61+ cells generated in vitro from CD34+ cells were then assayed for the levels of growth factors and proteases. Higher levels of transforming growth factor- (TGF-) and active matrix metalloproteinase-9 (MMP9) were observed in media conditioned with IMF CD61+ cells than normal or PV CD61+ cells. Both normal and IMF CD61+ cells produced similar levels of VEGF. MK derived TGF-B and MMP-9, therefore, likely contribute to the development of many pathological epiphenomena associated with IMF.
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