title: Pivotal contributions of megakaryocytes to the biology of idiopathic myelofibrosis.
abstract: In order to investigate the biologic processes underlying and resulting from the megakaryocytic hyperplasia that characterizes idiopathic myelofibrosis (IMF), peripheral blood CD34+ cells isolated from patients with IMF, polycythemia vera (PV), and G-CSF-mobilized healthy 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 overexpress the antiapoptotic 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-beta (TGF-beta) 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.
authors.affiliation: Hematology/Oncology Section, Department of Medicine, College of Medicine, University of Illinois at Chicago, IL, USA.
authors.forename: Stefan O
authors.initials: SO
authors.lastname: Ciurea
authors.forename: Delwin
authors.initials: D
authors.lastname: Merchant
authors.forename: Nadim
authors.initials: N
authors.lastname: Mahmud
authors.forename: Takefumi
authors.initials: T
authors.lastname: Ishii
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Wenyang
authors.initials: W
authors.lastname: Hu
authors.forename: Edward
authors.initials: E
authors.lastname: Bruno
authors.forename: Giovanni
authors.initials: G
authors.lastname: Barosi
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Xu
authors.forename: Ronald
authors.initials: R
authors.lastname: Hoffman
mesh_terms: D000328:Adult; D000368:Aged; D018952:Antigens, CD34; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006965:Hyperplasia / Q000378:metabolism / Q000473:pathology; D039661:Integrin beta3 / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D008533:Megakaryocytes / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D011087:Polycythemia Vera / Q000378:metabolism / Q000473:pathology; D055728:Primary Myelofibrosis / Q000378:metabolism* / Q000473:pathology; D013926:Thrombopoietin / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; C494811:BCL2L1 protein, human; D017077:Culture Media, Conditioned; C061248:ITGB3 protein, human; D039661:Integrin beta3; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D051020:bcl-X Protein; D016179:Granulocyte Colony-Stimulating Factor; D013926:Thrombopoietin; D020780:Matrix Metalloproteinase 9