Pivotal contributions of megakaryocytes to the biology of idiopathic myelofibrosis.
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.
Ciurea
Stefan O
SO
Hematology/Oncology Section, Department of Medicine, College of Medicine, University of Illinois at Chicago, IL, USA.
Merchant
Delwin
D
Mahmud
Nadim
N
Ishii
Takefumi
T
Zhao
Yan
Y
Hu
Wenyang
W
Bruno
Edward
E
Barosi
Giovanni
G
Xu
Mingjiang
M
Hoffman
Ronald
R
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
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