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Prepublished online as a Blood First Edition Paper on November 27, 2002; DOI 10.1182/blood-2002-06-1735.
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Blood, 1 April 2003, Vol. 101, No. 7, pp. 2784-2788
NEOPLASIA
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
From the Sidney Kimmel Comprehensive Cancer
Center at Johns Hopkins, Baltimore, MD; Medizinische Klinik IV,
Rheinisch-Westfaelische Technische Hochschule (RWTH) Aachen,
Aachen, Germany; and the Cancer Epigenetics Laboratory,
Molecular Pathology Program, Centro Nacional de Investigaciones
Oncologicas, Madrid, Spain.
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.
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