Epigenetic Silencing of a Proapoptotic Cell Adhesion Molecule, the Immunoglobulin Superfamily Member IGSF4, by Promoter CpG Methylation Protects Hodgkin Lymphoma Cells from Apoptosis
Epigenetic Silencing of a Proapoptotic Cell Adhesion Molecule, the Immunoglobulin Superfamily Member IGSF4, by Promoter CpG Methylation Protects Hodgkin Lymphoma Cells from Apoptosis
复制标题
DOI：
10.2353/ajpath.2010.100052
复制
发表时间：
2010-09-01
影响因子：
6
通讯作者：
Tao, Qian
中科院分区：
文献类型：
--
作者：
Murray, Paul G.;Fan, Yichao;Tao, Qian
霍奇金淋巴瘤（HL）的恶性霍奇金/里德-斯滕伯格（HRS）细胞被认为来源于生殖中心（GC）B细胞，但缺乏功能性B细胞受体的表达。由于凋亡是B细胞受体阴性GC B细胞的正常命运，因此消除凋亡的机制在HL发展中至关重要，例如某些促凋亡癌基因（包括肿瘤抑制基因）的表观遗传破坏。识别甲基化基因阐明致癌机制，并提供有价值的生物标志物，因此，我们进行了化学表观遗传筛选甲基化基因在HI。通过药理学去甲基化和表达谱分析。IGST 4/CADM 1/TSLC 1是免疫球蛋白超家族的促凋亡细胞粘附分子，与其他甲基化靶标一起鉴定。与正常GC B细胞中的表达相反，IGSF 4在细胞系、大多数原发性HL和3/5例显微解剖的HRS细胞中下调和甲基化，但在正常外周血单个核细胞中没有，在正常淋巴结中很少。我们还在14/18（78%）HL患者的血清中检测到IGSF 4甲基化，但在正常血清中很少检测到。IGSF 4的异位表达降低HL细胞的存活率并增加其对凋亡的敏感性。在甲基化淋巴瘤细胞中，通常在热休克应激处理后的IGSF 4诱导也被废除。因此，我们的数据表明，IGSF 4沉默CpG甲基化提供了一个抗凋亡信号的HRS细胞在HL发病机制中的重要性。(Am J Pathol 2010. 2010.100052）
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)