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Insulin-like growth factor binding protein-1 is elevated in patients with
polycythemia vera and stimulates erythroid burst formation in vitro
AM Mirza, S Ezzat and AA Axelrad
Department of Anatomy and Cell Biology, University of Toronto, Ontario,
Canada.
Previously, we found that, in the myeloproliferative disorder polycythemia
vera (PV), circulating erythroid progenitor cells were hypersensitive to
insulin-like growth factor I (IGF-I), an effect shown to occur through the
IGF-I receptor. Also, in cells of PV patients, the IGF-I receptor was
hyperphosphorylated on tyrosine residues under basal conditions, and its
tyrosine phosphorylation in response to exogenous IGF-I was strongly
augmented. Thus, because IGF-I appeared to play a role in the pathogenesis
of PV, we wished to assess its level in the circulation of these patients.
Normally, most of the circulating IGF-I is bound to specific high-affinity
IGF binding proteins that can regulate its activity. We determined the
circulating levels of IGF-I and two of its key binding proteins, IGFBP-1
and IGFBP-3. In two separate experiments, plasma samples from a total of 23
PV patients age- and sex-matched with 41 normal individuals were compared
by radioimmunoassay. The levels of IGFBP-1 in patients with PV (37.80 +/-
4.33 microg/L) were more than fourfold higher than in normals (9.34 +/-
1.34 microg/L) or patients with secondary erythrocytosis (9.47 +/- 1.96
microg/L), whereas the plasma concentrations of IGFBP-3 and IGF-I in these
patients were similar to those of normal subjects. Because circulating
IGFBP-1 levels may be influenced by insulin, we measured the concentrations
of insulin in the same samples. Our data showed that the elevation of
circulating IGFBP-1 in PV could not be attributed to low levels of insulin
in these patients. The substantial increase in concentration of IGFBP-1 was
confirmed on ligand blots performed with (125)I-IGF-I. IGFBP-1 can be
either inhibitory or stimulatory to the action of IGF-I under different
conditions. We reasoned that if IGFBP-1 were stimulatory for
erythropoiesis, an elevated IGFBP-1 level could help to explain the
increased sensitivity to IGF-I observed in PV. If IGFBP-1 were inhibitory,
it might suggest a compensatory mechanism in which a hyperphosphorylated
IGF-I receptor in PV might induce a negative modulator of IGF-I action, in
this case IGFBP-1. To distinguish between these two hypotheses, we titrated
the effect of IGFBP-1 in the presence of IGF-I with respect to erythroid
burst formation and found that IGFBP-1 was strikingly stimulatory. The
elevated level of IGFBP-1 coupled with its ability to stimulate erythroid
burst formation provide an attractive mechanism to account for the
increased sensitivity of erythroid progenitor cells to IGF-I and the
consequent overproduction of red blood cells characteristic of PV.
Volume 89,
Issue 6,
pp. 1862-1869,
03/15/1997
Copyright © 1997 by The American Society of Hematology
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