SOCS1 and SHP1 hypermethylation in multiple myeloma:: implications for epigenetic activation of the Jak/STAT pathway
SOCS1 and SHP1 hypermethylation in multiple myeloma:: implications for epigenetic activation of the Jak/STAT pathway
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DOI：
10.1182/blood-2003-06-2007
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发表时间：
2004-06-15
期刊：
影响因子：
20.3
通讯作者：
Kwong, YL
中科院分区：
文献类型：
--
作者：
Chim, CS;Fung, TK;Kwong, YL
SOCS1 和 SHP1 负向调节 Janus 激酶/信号转导器和转录激活子 (Jak/STAT) 信号通路。研究了启动子高甲基化导致 SOCS1 和 SHP1 在骨髓瘤中表观遗传失活的作用。使用甲基化特异性聚合酶链反应 (MSP) 来定义 34 个诊断性骨髓瘤样本中的 SOCS1 和 SHP1 甲基化。对于 SOCS1，翻译起始位点 3' 的 MSP 引物不可靠，并且在正常对照中给出阳性结果。然而，尽管没有骨髓瘤样本显示甲基化，但 5' 启动子区域的引物是特异性的。对于 SHP1，34 个骨髓瘤样本中有 27 个 (79.4%) 显示 SHP1 高甲基化。在 U266 人骨髓瘤系中研究了 SHP1 甲基化的生物学意义。 U266含有完全甲基化的SHP1。此外，STAT3 存在组成型磷酸化。 5-氮杂胞苷处理导致第2至第5天SHP1进行性去甲基化，随后逆转录聚合酶链式反应（RT-PCR）显示SHP1的重新表达增加。伴随着SHP1的增加，磷酸化STAT3发生平行下调，因此到第5天几乎检测不到磷酸化STAT3。有和没有 SHP1 甲基化的患者的总生存期相似。 SHP1甲基化导致Jak/STAT通路的表观遗传激活，可能在骨髓瘤的发病机制中具有初步作用，这一点应通过原发性骨髓瘤样本的功能研究进一步证实。 (C) 2004 年，美国血液学会。
SOCS1 and SHP1 negatively regulate the Janus kinase/signal transducer and activator of transcription (Jak/STAT) signaling pathway. The role of promoter hypermethylation leading to epigenetic inactivation of SOCS1 and SHP1 in myeloma was investigated. The methylation-specific polymerase chain reaction (MSP) was used to define SOCS1 and SHP1 methylation in 34 diagnostic myeloma samples. For SOCS1, MSP primers 3' to the translation start site were unreliable and gave positive results in normal controls. However, primers in the 5' promoter region were specific, although no myeloma samples showed methylation. For SHP1, 27 of 34 (79.4%) myeloma samples showed SHP1 hypermethylation. The biologic significance of SHP1 methylation was investigated in the U266 human myeloma line. U266 contained completely methylated SHP1. Furthermore, there was constitutive STAT3 phosphorylation. Treatment with 5-azacytidine led to progressive demethylation of SHP1 on days 2 to 5, with consequent increasing reexpression of SHP1 as shown by reverse transcription-polymerase chain reaction (RT-PCR), Concomitant with increasing SHP1, a parallel down-regulation of phosphorylated STAT3 occurred, so that by day 5 phosphorylated STAT3 was barely detectable. The overall survivals of patients with and without SHP1 methylation were similar. SHP1 methylation leading to epigenetic activation of the Jak/STAT pathway, might have a tentative role in the pathogenesis of myeloma, which should be further confirmed by functional studies in primary myeloma samples. (C) 2004 by The American Society of Hematology.