Journal
BRITISH JOURNAL OF HAEMATOLOGY
Volume 161, Issue 3, Pages 348-356Publisher
WILEY
DOI: 10.1111/bjh.12262
Keywords
SOCS3; methylation; mantle cell lymphoma; STAT3; NF-B
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Funding
- Canadian Cancer Society Research Institute
- Alberta Cancer Foundation
- Canadian Institute of Health Research
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The significance of loss of SOCS3, a negative regulator of signalling pathways including those of STAT3 and NF-B, was examined in mantle cell lymphoma (MCL). The protein expression and gene methylation status of SOCS3 were detected using immunohistochemistry/Western blots and methylation-specific polymerase chain reaction, respectively. To evaluate its functional importance, SOCS3 was restored in two SOCS3-negative MCL cell lines using a lentiviral vector. Loss of SOCS3 protein expression was found in 3/4 MCL cell lines and 18/33 (54 center dot 5%) tumours. SOCS3 was found consistently methylated in cell lines (3/4) and tumours (7/7) negative for SOCS3, and was unmethylated in all SOCS3-positive cell line (1/1) and tumours (5/5) examined. Treatment of all three SOCS3-negative cell lines with 2-deoxy-5-azacytidine restored SOCS3 expression. SOCS3 is biologically important in MCL, as lentiviral transfer of SOCS3 in SOCS3-negative cell lines increased their apoptotic activity, downregulated nuclear factor (NF)-B-p65, cyclin D1 (CCND1), BCL2 and BCL-XL (BCL2L1), and substantially dampened interleukin 10-induced STAT3 activation. In 19 patients aged 69years at time of diagnosis, we found that those that carried SOCS3-negative tumours showed a trend toward a worse outcome (P=0 center dot 1, log-rank).
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