Epigenetic silencing of a proapoptotic cell adhesion molecule, the immunoglobulin superfamily member IGSF4, by promoter CpG methylation protects hodgkin lymphoma cells from apoptosis

Paul G. Murray, Yichao Fan, Gillian Davies, Jianming Ying, Hua Geng, Ka Man Ng, Hongyu Li, Zifen Gao, Wenbin Wei, Shikha Bose, Jennifer Anderton, Georgia Kapatai, Gary Reynolds, Akihiko Ito, Teresa Marafioti, Ciaran B.J. Woodman, Richard Ambinder, Qian Tao

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

The malignant Hodgkin/Reed-Sternberg (HRS) cells of Hodgkin lymphoma (HL) are believed to derive from germinal center (GC) B cells, but lack expression of a functional B cell receptor. As apoptosis is the normal fate of B-cell receptor - negative GC B cells, mechanisms that abrogate apoptosis are thus critical in HL development, such as epigenetic disruption of certain pro-apoptotic cancer genes including tumor suppressor genes. Identifying methylated genes elucidates oncogenic mechanisms and provides valuable biomarkers; therefore, we performed a chemical epigenetic screening for methylated genes in HL through pharmacological demethylation and expression profiling. IGSF4/CADM1/TSLC1, a pro-apoptotic cell adhesion molecule of the immunoglobulin superfamily, was identified together with other methylated targets. In contrast to its expression in normal GC B cells, IGSF4 was down-regulated and methylated in HL cell lines, most primary HL, and microdissected HRS cells of 3/5 cases, but not in normal peripheral blood mononuclear cells and seldom in normal lymph nodes. We also detected IGSF4 methylation in sera of 14/18 (78%) HL patients but seldom in normal sera. Ectopic IGSF4 expression decreased HL cells survival and increased their sensitivity to apoptosis. IGSF4 induction that normally follows heat shock stress treatment was also abrogated in methylated lymphoma cells. Thus, our data demonstrate that IGSF4 silencing by CpG methylation provides an anti-apoptotic signal to HRS cells important in HL pathogenesis.

Original languageEnglish (US)
Pages (from-to)1480-1490
Number of pages11
JournalAmerican Journal of Pathology
Volume177
Issue number3
DOIs
StatePublished - Sep 2010

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Murray, P. G., Fan, Y., Davies, G., Ying, J., Geng, H., Ng, K. M., Li, H., Gao, Z., Wei, W., Bose, S., Anderton, J., Kapatai, G., Reynolds, G., Ito, A., Marafioti, T., Woodman, C. B. J., Ambinder, R., & Tao, Q. (2010). Epigenetic silencing of a proapoptotic cell adhesion molecule, the immunoglobulin superfamily member IGSF4, by promoter CpG methylation protects hodgkin lymphoma cells from apoptosis. American Journal of Pathology, 177(3), 1480-1490. https://doi.org/10.2353/ajpath.2010.100052