SOCS-1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma
SOCS-1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma
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DOI：
10.1182/blood-2002-06-1735
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发表时间：
2003-04-01
期刊：
影响因子：
20.3
通讯作者：
Herman, JG
中科院分区：
文献类型：
--
作者：
Galm, O;Yoshikawa, H;Herman, JG
细胞因子信号转导抑制蛋白(SOCS)家族参与了多种细胞因子途径的负性调控，特别是转录激活的受体相关酪氨酸激酶/信号转导和转录激活因子(JAK/STAT)途径。SOCS-1(也称为JAB和SSI-1)通过多种细胞因子抑制信号传导。由于先前观察到肝细胞癌中SOCS-1的高甲基化相关失活，以及白介素6(IL-6)作为多发性骨髓瘤(MM)生存因子的关键作用，我们在MM细胞系和原代MM样本中检测了SOCS-1基因的CpG岛甲基化。在依赖IL-6的MM细胞系U266和XG1中发现SOCS-1甲基化异常，这与转录沉默有关。去甲基化试剂5-氮杂-2‘-脱氧胞苷(DAC)处理这些细胞系后，SOCS-1的表达上调。造血细胞系中与甲基化相关的SOCS-1失活与对化学JAK抑制剂AG490更敏感相关。应用甲基化特异性聚合酶链式反应(MSP)，我们发现62.9%(23/35)的MM患者SOCS-1高甲基化。而恶性淋巴瘤中仅有3.2%(2/62)出现SOCS-1高甲基化，而正常外周血白细胞和骨髓细胞中均未见SOCS-1甲基化。我们得出结论：在多发性骨髓瘤患者中，SOCS-1经常被高甲基化失活。SOCS-1基因的沉默可能会削弱JAK/STAT通路的负调控，从而导致对细胞因子的更大反应，从而支持MM细胞的生存和扩张。
The suppressor of cytokine signaling (SOCS) family of proteins has been implicated in the negative regulation of several cytokine pathways, particularly the receptor-associated tyrosine kinase/signal transducer and activator of transcription (Jak/STAT) pathways of transcriptional activation. SOCS-1 (also known as JAB and SSI-1) inhibits signaling by many cytokines. Because of the previously observed hypermethylation-associated inactivation of SOCS-1 in hepatocellular carcinoma and the critical role of interleukin-6 (IL-6) as a survival factor in multiple myeloma (MM), we examined CpG island methylation of the SOCS-1 gene in MM cell lines and primary MM samples. Aberrant SOCS-1 methylation was found in the IL-6-dependent MM cell lines U266 and XG1, which correlated with transcriptional silencing. Treatment of these cell lines with the demethylating agent 5-aza-2'-deoxycytidine (DAC) up-regulated SOCS-1 expression. Methylation-associated inactivation of SOCS-1 in hematopoietic cell lines correlated with greater sensitivity to the chemical JAK inhibitor AG490. Using methylation-specific polymerase chain reaction (MSP), we found that SOCS-1 is hypermethylated in 62.9% (23/35) of MM patient samples. In contrast, methylation analysis of malignant lymphomas of various histologies revealed SOCS-1 hypermethylation in only 3.2% (2/62), and there was no methylation of SOCS-1 in normal peripheral blood leukocytes or bone marrow cells. We conclude that SOCS-1 is frequently inactivated by hypermethylation in MM patients. Silencing of the SOCS-1 gene may impair negative regulation of the Jak/ STAT pathway and therefore result in greater responsiveness to cytokines, thus supporting survival and expansion of MM cells.