Overexpression of SOCS-2 and SOCS-3 genes reverses erythroid overgrowth and IGF-I hypersensitivity of primary polycythemia vera (PV) cells

Abstract

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.

Sox6 enhances erythroid differentiation in human erythroid progenitors

“…38,47-49 38,40,41 ) between the genes/pathways studied in the present report. SOCS3 interferes with the EPO/JAK/STAT pathway by binding the EPO receptor (EpoR) and JAK, 38 and it interferes with IGF-1 signaling by binding IGF-1R.…”

“…by guest www.bloodjournal.org From Among pathways controlled by SOCS3, there are those that involve EPO/JAK2/STAT5 and IGF-1/IGF-1R, both of which are required for erythroid progenitor cell survival. 38,41 The present experiments in K562 cells show that the effects of Sox6 on proliferation are not mediated by alteration of the EPO/JAK2/ STAT5 pathway (supplemental Figure 5). However, in K562 cells, in which Bcr/Abl promotes autocrine IGF-1 signaling, thus stimulating cell proliferation and protecting cells from apoptosis, 40 IGF-1 mRNA was reduced when Sox6 or SOCS3 was overexpressed ( Figure 6).…”

SOCS2: inhibitor of JAK2V617F-mediated signal transduction

“…25 In polycythemia vera, low-level expression of SOCS2 in insulin-like growth factor-I-treated BFU-E colonies contributes to IGF-I hypersensitivity and to erythroid overgrowth. 26 These observations suggest that the oncogenic effect of the JAK2V617F mutation may be amplified by downregulation of SOCS2. The exact mode of action underlying SOCS2 inhibition of JAK2V617F signaling remains elusive.…”

Epigenetic inactivation of suppressors of cytokine signalling in Philadelphia‐negative chronic myeloproliferative disorders

“…Remarkably, a defect in SOCS3 expression has been recently proposed as a relevant factor for the insulin-like growth factor-1 (IGF-1) hypersensitivity characteristic of PV (Usenko et al, 2007). Also, in vitro inactivation of SOCS3 relieves the SOCS3-mediated inhibition exerted upon the signalling cascade mediated by the Eporeceptor (Sasaki et al, 2000).…”