Overexpression of SOCS-2 and SOCS-3 genes reverses erythroid overgrowth and IGF-I hypersensitivity of primary polycythemia vera (PV) cells.
Polycythemia vera (PV), an acquired, chronic, clonal disorder arising in a multipotential hematopoietic progenitor cell, is characterized by hyperplasia of three major myeloid lineages, with a pronounced increase in cells of the erythroid lineage. Erythroid progenitor cells in PV are strikingly hypersensitive to insulin-like growth factor-I (IGF-I); this effect is specific and is mediated through the IGF-I receptor. To investigate the possibility that in PV the increase in number of erythroid progenitors and their hypersensitivity to IGF-I result from a defect in negative regulation of cytokine activity, we examined the expression of members of the SOCS gene family. Circulating mononuclear cells, grown in serum-free methylcellulose medium in the presence of IGF-I, produced BFU-E-derived colonies whose cells revealed a reduction of SOCS-2 and SOCS-3 expression in PV only. Overexpression of these genes in transfected PV cells reduced their erythroid overgrowth and IGF-I hypersensitivity. We hypothesize that a defect in expression of SOCS-2 and SOCS-3 genes may be crucial for the IGF-I hypersensitivity and progressive increase in erythroid cell population size characteristic of PV.
Usenko
Tatiana
T
Department of Molecular and Cellular Biology, Sunnybrook and Women's College Health Sciences Centre, Toronto, Canada.
Eskinazi
Denise
D
Correa
Paulo N
PN
Amato
Dominick
D
Ben-David
Yaacov
Y
Axelrad
Arthur A
AA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D049109:Cell Proliferation / Q000187:drug effects*; D041905:Erythroid Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism / Q000473:pathology; D011087:Polycythemia Vera / Q000276:immunology / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
C106643:SOCS2 protein, human; C106644:SOCS3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007334:Insulin-Like Growth Factor I