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

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Epigenetic Silencing of a Proapoptotic Cell Adhesion Molecule, the Immunoglobulin Superfamily Member IGSF4, by Promoter CpG Methylation Protects Hodgkin Lymphoma Cells from Apoptosis. / Murray, Paul; Fan, Y; Davies, G; Ying, J; Geng, H; Ng, KM; Li, H; Gao, Z; Wei, Wenbin; Bose, S; Anderton, Jennifer; Kapatai, Georgia; Reynolds, Gary; Ito, A; Marafioti, T; Woodman, Ciaran; Ambinder, R; Tao, Q.

In: The American Journal of Pathology, Vol. 177, No. 3, 01.09.2010, p. 1480-1490.

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Murray, Paul ; Fan, Y ; Davies, G ; Ying, J ; Geng, H ; Ng, KM ; Li, H ; Gao, Z ; Wei, Wenbin ; Bose, S ; Anderton, Jennifer ; Kapatai, Georgia ; Reynolds, Gary ; Ito, A ; Marafioti, T ; Woodman, Ciaran ; Ambinder, R ; Tao, Q. / Epigenetic Silencing of a Proapoptotic Cell Adhesion Molecule, the Immunoglobulin Superfamily Member IGSF4, by Promoter CpG Methylation Protects Hodgkin Lymphoma Cells from Apoptosis. In: The American Journal of Pathology. 2010 ; Vol. 177, No. 3. pp. 1480-1490.

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@article{31611e4e113946f8b8995a85d44b839b,
title = "Epigenetic Silencing of a Proapoptotic Cell Adhesion Molecule, the Immunoglobulin Superfamily Member IGSF4, by Promoter CpG Methylation Protects Hodgkin Lymphoma Cells from Apoptosis",
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 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)",
author = "Paul Murray and Y Fan and G Davies and J Ying and H Geng and KM Ng and H Li and Z Gao and Wenbin Wei and S Bose and Jennifer Anderton and Georgia Kapatai and Gary Reynolds and A Ito and T Marafioti and Ciaran Woodman and R Ambinder and Q Tao",
year = "2010",
month = sep,
day = "1",
doi = "10.2353/ajpath.2010.100052",
language = "English",
volume = "177",
pages = "1480--1490",
journal = "The American Journal of Pathology",
issn = "0002-9440",
publisher = "American Society for Investigative Pathology",
number = "3",

}

RIS

TY - JOUR

T1 - Epigenetic Silencing of a Proapoptotic Cell Adhesion Molecule, the Immunoglobulin Superfamily Member IGSF4, by Promoter CpG Methylation Protects Hodgkin Lymphoma Cells from Apoptosis

AU - Murray, Paul

AU - Fan, Y

AU - Davies, G

AU - Ying, J

AU - Geng, H

AU - Ng, KM

AU - Li, H

AU - Gao, Z

AU - Wei, Wenbin

AU - Bose, S

AU - Anderton, Jennifer

AU - Kapatai, Georgia

AU - Reynolds, Gary

AU - Ito, A

AU - Marafioti, T

AU - Woodman, Ciaran

AU - Ambinder, R

AU - Tao, Q

PY - 2010/9/1

Y1 - 2010/9/1

N2 - 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)

AB - 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)

U2 - 10.2353/ajpath.2010.100052

DO - 10.2353/ajpath.2010.100052

M3 - Article

C2 - 20709797

VL - 177

SP - 1480

EP - 1490

JO - The American Journal of Pathology

JF - The American Journal of Pathology

SN - 0002-9440

IS - 3

ER -