Galm Oliver, Yoshikawa Hirohide, Esteller Manel, Osieka Rainhardt, Herman James G
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA.
Blood. 2003 Apr 1;101(7):2784-8. doi: 10.1182/blood-2002-06-1735. Epub 2002 Nov 27.
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.
细胞因子信号转导抑制因子（SOCS）蛋白家族与多种细胞因子信号通路的负调控有关，特别是与转录激活的受体相关酪氨酸激酶/信号转导子和转录激活子（Jak/STAT）通路有关。SOCS-1（也称为JAB和SSI-1）可抑制多种细胞因子的信号传导。鉴于先前在肝细胞癌中观察到SOCS-1因高甲基化而失活，以及白细胞介素-6（IL-6）在多发性骨髓瘤（MM）中作为生存因子的关键作用，我们检测了MM细胞系和原发性MM样本中SOCS-1基因的CpG岛甲基化情况。在依赖IL-6的MM细胞系U266和XG1中发现了异常的SOCS-1甲基化，这与转录沉默相关。用去甲基化剂5-氮杂-2'-脱氧胞苷（DAC）处理这些细胞系可上调SOCS-1的表达。造血细胞系中SOCS-1的甲基化相关失活与对化学JAK抑制剂AG490的更高敏感性相关。使用甲基化特异性聚合酶链反应（MSP），我们发现62.9%（23/35）的MM患者样本中SOCS-1发生了高甲基化。相比之下，对各种组织学类型的恶性淋巴瘤进行甲基化分析发现，只有3.2%（2/62）的样本中SOCS-1发生了高甲基化，而正常外周血白细胞或骨髓细胞中未发现SOCS-1甲基化。我们得出结论，MM患者中SOCS-1经常因高甲基化而失活。SOCS-1基因的沉默可能会损害Jak/STAT通路的负调控，从而导致对细胞因子的反应性增强，进而支持MM细胞的存活和增殖。
