The family of suppressor of
cytokine signaling (
SOCS) proteins negatively regulates
cytokine signaling in different cellular pathways including
interleukin-6 (IL-6). Since
IL-6 plays an essential role in regulating growth and survival of
multiple myeloma (MM) cells, methylation-associated dysregulation of SOCS3 may contribute to the malignant phenotype of MM cells. We used methylation-specific PCR (MSP) to assess the methylation status of the SOCS3 CpG island in five MM cell lines and 70 patient samples. Additional
bisulfite sequencing and
RNA expression analysis using
reverse transcriptase polymerase chain reaction was performed in two cell lines. We identified aberrant SOCS3 methylation in 3/5 MM cell lines. Methylation of SOCS3 in cell lines was associated with transcriptional downregulation. Treatment of OPM-2 cells, which carry a methylated SOCS3 gene, with the demethylating agent
5-aza-2'-deoxycytidine restored SOCS3 expression in association with partial demethylation. In patient samples with malignant plasma cell disorders, SOCS3 was methylated in 5/70 (7.1 %) cases, while there was no aberrant SOCS3 methylation in normal peripheral blood and non-malignant bone marrow cells. We found an association of SOCS3 methylation with extramedullary manifestations (p = 0.03),
plasma cell leukemia (p = 0.003), elevated LDH (p = 0.001), increased
creatinine ( p = 0.01) and remarkably shortened survival (6.9 vs. 56.1 months, HR 5.9, p = 0.0007). Our findings reveal a novel epigenetic event possibly implicated in the pathogenesis of MM and representing a potential prognostic
biomarker. Epigenetic dysregulation of the SOCS3 gene may interfere with the cellular response to the complex
cytokine network thus supporting survival and expansion of MM cells.