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Prepublished online as a Blood First Edition Paper on November 27, 2002; DOI 10.1182/blood-2002-06-1735. This Article Full Text (PDF) All Versions of this Article: 2002-06-1735v1 101/7/2784    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Galm, O. Articles by Herman, J. G Search for Related Content PubMed PubMed Citation Articles by Galm, O. Articles by Herman, J. G Related Collections Related Letter in Blood Online Social Bookmarking                   What's this? Submitted June 12, 2002 Accepted November 14, 2002 SOCS-1, a negative regulator of cytokine signaling, is frequently silenced by methylation in multiple myeloma Oliver Galm, Hirohide Yoshikawa, Manel Esteller, Rainhardt Osieka, and James G Herman* Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA; Medizinische Klinik IV, Rheinisch-Westfaelische Technische Hochschule Aachen, Aachen, Germany Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA; Cancer Epigenetics Laboratory, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain Medizinische Klinik IV, Rheinisch-Westfaelische Technische Hochschule Aachen, Aachen, Germany * Corresponding author; email: hermanji{at}jhmi.edu. 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 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) upregulated 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 PCR (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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Letter in Blood Online: Silencing of the SOCS-1 gene by CpG methylation? 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