Quentmeier H, Geffers R, Jost E, Macleod R A F, Nagel S, Röhrs S, Romani J, Scherr M, Zaborski M, Drexler H G
DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany.
Leukemia. 2008 Dec;22(12):2169-75. doi: 10.1038/leu.2008.226. Epub 2008 Sep 4.
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.
Janus激酶2（JAK2）V617F激活突变（JAK2mu）发生于骨髓增殖性疾病（MPD）和骨髓增生异常综合征（MDS）。细胞系MB - 02、MUTZ - 8、SET - 2和UKE - 1携带JAK2V617F，源自具有MPD/MDS病史的患者。对于I类细胞因子受体阳性细胞中JAK2V617F的表达是细胞因子非依赖性的唯一前提这一共识提出挑战的是，四个JAK2mu细胞系中有两个依赖生长因子。这些细胞系在JAK2/STAT5激活方面类似于JAK2野生型细胞：细胞因子剥夺导致去磷酸化，而促红细胞生成素或粒细胞集落刺激因子诱导JAK2和STAT5磷酸化。细胞因子非依赖性与JAK/STAT途径抑制剂细胞因子信号转导抑制因子2（SOCS2）的低表达相关，细胞因子依赖性与高表达相关，提示MPD细胞的细胞因子非依赖性存在两步机制：（i）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的负调节因子起作用的是，SOCS2敲低诱导JAK2mu细胞中组成型STAT5磷酸化。据报道，CpG岛高甲基化促进恶性疾病中SOCS基因沉默。因此，在两个细胞因子非依赖性细胞系之一以及七名MPD患者中的两名患者中，我们发现SOCS2高甲基化与启动子对转录因子的可及性降低相关。我们的结果提供了确凿证据，表明SOCS2的表观遗传下调可能是细胞因子非依赖性MPD克隆发生过程中的重要第二步。
