SOCS2: inhibitor of JAK2V617F-mediated signal transduction
SOCS2: inhibitor of JAK2V617F-mediated signal transduction
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DOI：
10.1038/leu.2008.226
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发表时间：
2008-12-01
期刊：
影响因子：
11.4
通讯作者：
Drexler, H. G.
中科院分区：
文献类型：
--
作者：
Quentmeier, H.;Geffers, R.;Drexler, H. G.
Janus激酶2 (JAK2) v617f激活突变（JAK2mu）发生在骨髓增生性疾病（MPDs）和骨髓增生异常综合征（mds）中。MB-02、MUTZ-8、SET-2和UKE-1细胞系携带JAK2V617F，来自有MPD/MDS病史的患者。在一类细胞因子受体阳性细胞中，JAK2V617F的表达是细胞因子独立的唯一前提，这一共识受到挑战，四种JAK2mu细胞系中有两种是生长因子依赖的。这些细胞系在JAK2/STAT5激活方面与JAK2wt细胞相似：细胞因子剥夺影响去磷酸化，而红细胞生成素或粒细胞集落刺激因子诱导JAK2和STAT5磷酸化。细胞因子独立性与JAK/STAT通路抑制剂细胞因子信号传导抑制因子2 （SOCS2）的低表达和高表达相关，表明MPD细胞细胞因子独立性的两步机制：(i)致癌基因JAK2V617F的激活和（ii）肿瘤抑制基因SOCS2的失活。证实SOCS2作为JAK2V617F负调控因子起作用，SOCS2敲低诱导JAK2mu细胞中STAT5的组成磷酸化。据报道，CpG岛高甲基化可促进恶性疾病中SOCS基因沉默。因此，在两个细胞因子独立细胞系中的一个和七个MPD患者中的两个中，我们发现SOCS2超甲基化与转录因子的启动子通路减少相关。我们的研究结果提供了确凿的证据，表明SOCS2表观遗传下调可能是细胞因子非依赖性MPD克隆发生的重要第二步。
Janus kinase 2 (JAK2)V617F-activating mutations (JAK2mu) occur in myeloproliferative disorders (MPDs) and myelodysplastic syndromes (MDSs). Cell lines MB-02, MUTZ-8, SET-2 and UKE-1 carry JAK2V617F and derive from patients with MPD/MDS histories. Challenging the consensus that expression of JAK2V617F is the sole precondition for cytokine independence in class I cytokine receptor-positive cells, two of four of the JAK2mu cell lines were growth factor-dependent. These cell lines resembled JAK2wt cells regarding JAK2/STAT5 activation: cytokine deprivation effected dephosphorylation, whereas erythropoetin or granulocyte colony-stimulating factor induced phosphorylation of JAK2 and STAT5. Cytokine independence correlated with low expression and cytokine dependence with high expression of the JAK/STAT pathway inhibitor suppressor of cytokine signaling 2 (SOCS2) suggesting a two-step mechanism for cytokine independence of MPD cells: (i) activation of the oncogene JAK2V617F and (ii) inactivation of the tumor suppressor gene SOCS2. Confirming that SOCS2 operates as a negative JAK2V617F regulator, SOCS2 knockdown induced constitutive STAT5 phosphorylation in JAK2mu cells. CpG island hypermethylation is reported to promote SOCS gene silencing in malignant diseases. Accordingly, in one of two cytokine-independent cell lines and in two of seven MPD patients, we found SOCS2 hypermethylation associated with reduced promoter access to transcription factors. Our results provide solid evidence that SOCS2 epigenetic downregulation might be an important second step in the genesis of cytokine-independent MPD clones.