Centre for Infection and Immunity, Queen's University, Belfast, Northern Ireland.
Br J Haematol. 2009 Nov;147(4):450-8. doi: 10.1111/j.1365-2141.2009.07860.x. Epub 2009 Sep 5.
Recently several different JAK2 exon12 mutations have been identified in V617F negative polycythaemia vera (PV) or idiopathic erythrocytosis (IE) patients. The patients present with erythrocytosis, ligand-independent cell growth and low serum erythropoietin (EPO) levels. Within this group, a deletion of amino acids 542-543 (N542-E543del) of JAK2 is most prevalent. We have previously shown that in the presence of JAK2(V617F), suppressor of cytokine signalling 3 (SOCS3) is unable to negatively regulate EPO signalling and proliferation of V617F-expressing cells. Here we report a PV patient heterozygous for the somatic JAK2(N542-E543del) mutation and a previously unreported germline mutation within the SH2 domain of SOCS3 (F136L). Interestingly, the SOCS3(F136L) mutation was detected in a Japanese myeloproliferative disorder patient cohort at double the frequency of healthy controls. Cells expressing SOCS3(F136L) had markedly elevated EPO-induced proliferation and extended EPO-induced JAK2 phosphorylation. Additionally, compared to wild-type SOCS3, mutant SOCS3 had an extended half-life in the presence of JAK2 and JAK2(N542-E543del). Our findings suggest that this loss-of-function SOCS3 mutation may have contributed to disease onset by causing deregulated JAK2 signalling in the presence of a constitutively active JAK2(N542-E543del) mutant.
最近，在 V617F 阴性真性红细胞增多症（PV）或特发性红细胞增多症（IE）患者中发现了几种不同的 JAK2 外显子 12 突变。这些患者表现为红细胞增多症、配体非依赖性细胞生长和低血清促红细胞生成素（EPO）水平。在这一组中，JAK2 的氨基酸 542-543 缺失（N542-E543del）最为常见。我们之前已经表明，在存在 JAK2（V617F）的情况下，细胞因子信号转导抑制因子 3（SOCS3）无法负调控 EPO 信号转导和 V617F 表达细胞的增殖。在这里，我们报告了一例杂合体细胞 JAK2（N542-E543del）突变的 PV 患者，以及 SOCS3 的 SH2 结构域中以前未报道的种系突变（F136L）。有趣的是，SOCS3（F136L）突变在日本骨髓增殖性疾病患者队列中的检出率是健康对照的两倍。表达 SOCS3（F136L）的细胞具有明显升高的 EPO 诱导增殖和延长的 EPO 诱导 JAK2 磷酸化。此外，与野生型 SOCS3 相比，突变 SOCS3 在 JAK2 和 JAK2（N542-E543del）存在的情况下半衰期延长。我们的研究结果表明，这种丧失功能的 SOCS3 突变可能通过在存在组成性激活的 JAK2（N542-E543del）突变体时导致 JAK2 信号转导失调，从而导致疾病的发生。
