The myeloproliferative disorder-associated JAK2 V617F mutant escapes negative regulation by suppressor of cytokine signaling 3

被引:92
作者
Hookham, Michelle B.
Elliott, Joanne
Suessmuth, Yvonne
Staerk, Judith
Ward, Alister C.
Vainchenker, William
Percy, Melanie J.
McMullin, Mary Frances
Constantinescu, Stefan N.
Johnston, James A.
机构
[1] Queens Univ Belfast, Ctr Canc Res & Cell Biol, Infect & Immun Grp, Belfast BT9 7BL, Antrim, North Ireland
[2] Ludwig Inst Canc Res, Brussels, Belgium
[3] Catholic Univ Louvain, Christian de Duve Inst Cellular Pathol, Brussels, Belgium
[4] Deakin Univ, Sch Life & Environm Sci, Burwood, Australia
[5] Belfast City Hosp, Belfast BT9 7AD, Antrim, North Ireland
[6] Inst Gustave Roussy, INSERM U790, Villejuif, France
基金
英国惠康基金;
关键词
D O I
10.1182/blood-2006-08-039735
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The somatic JAK2 valine-to-phenylalanine (V617F) mutation has been detected in up to 90% of patients with polycythemia and in a sizeable proportion of patients with other myeloproliferative disorders such as essential thrombocythemia and idiopathic myelofibrosis. Suppressor of cytokine signaling 3 (SOCS3) is known to be a strong negative regulator of erythropoietin (EPO) signaling through interaction with both the EPO receptor (EPOR) and JAK2. We report here that JAK2 V617F cannot be regulated and that its activation is actually potentiated in the presence of SOCS3. Instead of acting as a suppressor, SOCS3 enhanced the proliferation of cells expressing both JAK2 V617F and EPOR. Additionally, although SOCS1 and SOCS2 are degraded in the presence of JAK2 V617F, turnover of SOCS3 is inhibited by the JAK2 mutant kinase and this correlated with marked tyrosine phosphorylation of SOCS3 protein. We also observed constitutive tyrosine phosphorylation of SOCS3 in peripheral blood mononuclear cells (PBMCs) derived from patients homozygous for the JAK2 V617F mutant. These findings suggest that the JAK2 V617F has overcome normal SOCS regulation by hyper-phosphorylating SOCS3, rendering it unable to inhibit the mutant kinase. Thus, JAK2 V617F may even exploit SOCS3 to potentiate its myeloproliferative capacity.
引用
收藏
页码:4924 / 4929
页数:6
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