Epigenetic Silencing of a Proapoptotic Cell Adhesion Molecule, the Immunoglobulin Superfamily Member IGSF4, by Promoter CpG Methylation Protects Hodgkin Lymphoma Cells from Apoptosis
Publication in refereed journal



摘要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 HI. through pharmacological demethylation and expression profiling. IGST4/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 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. (Am J Pathol 2010. 177:1480-1490; 10.2353/ajpath.2010.100052)
著者Murray PG, Fan YC, Davies G, Ying JM, Geng H, Ng KM, Li HY, Gao ZF, Wei WB, Bose S, Anderton J, Kapatai G, Reynolds G, Ito A, Marafioti T, Woodman CBJ, Ambinder R, Tao QA
期刊名稱American Journal of Pathology
頁次1480 - 1490
Web of Science 學科類別Pathology; PATHOLOGY

上次更新時間 2021-11-09 於 00:32