Alterations of the insulin-like growth factor system in patients with polycythemia vera.
The molecular etiology of Polycythemia vera (PV) is still undetermined. Recently, enhanced tyrosine phosphorylation of the insulin-like growth factor-I receptor (IGF-IR) has been shown in PV bone marrow progenitors and peripheral blood mononuclear cells (PBMNC), and elevated levels of IGF binding protein-1 (IGFBP-1) in the serum of PV patients have been reported. To identify further alterations of circulating IGFBPs, the IGFBP profile in the serum of 12 PV patients was compared with age- and sex-matched controls by Western ligand blot (WLB), two-dimensional WLB, IGFBP-3 immunoblot and specific RIA for IGFBP-1, -2, -3 and IGFBP-4. To elucidate a role for the IGF-IR in the pathogenesis of PV, basal and IGF-I stimulated tyrosine phosphorylation of the IGF-IR beta-subunit in PBMNC of PV patients or controls was determined by WLB. Furthermore, exons 2, 3 and 15-21 of the IGF-IR were screened for mutations by PCR-single strand conformation polymorphism analysis (PCR-SSCP). We found alterations of the IGFBP profile in the serum of eight out of 12 examined patients including elevated levels of IGFBP-1, -2 and -4, decreased levels of IGFBP-3 and an increase in IGFBP-3 fragment. However, no differences in tyrosine phosphorylation of the IGF-IR in PV patients, neither basal nor IGF-I induced, were detected. Furthermore, no mutations within the screened exons of the IGF-IR could be identified by PCR-SSCP. We conclude that there is no direct impairment of IGF-IR structure or function, but an altered IGFBP profile in a significant portion of PV patients which might contribute to the pathogenesis of PV in these patients.
Michl
P
P
Medical Department II, Klinikum Grosshadern, University of Munich, Munich, Germany. patrick.michl@medizin.uni-ulm.de
Spoettl
G
G
Engelhardt
D
D
Weber
M M
MM
D000328:Adult; D000368:Aged; D015153:Blotting, Western; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D018969:Insulin-Like Growth Factor Binding Proteins / Q000097:blood / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011087:Polycythemia Vera / Q000378:metabolism* / Q000503:physiopathology*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011863:Radioimmunoassay; D017526:Receptor, IGF Type 1 / Q000235:genetics
D018969:Insulin-Like Growth Factor Binding Proteins; D019000:Phosphotyrosine; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1