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Epigenetic silencing of the interferon regulatory factor ICSBP/IRF8 in human multiple myeloma

Marina Tshuikina1, Helena Jernberg-Wiklund, Kenneth Nilsson

  • 1Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

Experimental Hematology
|October 17, 2008
PubMed
Abstract

Insights

Silencing of interferon regulatory factor 8 (IRF8) occurs in most multiple myeloma cell lines and patient cells, often due to DNA methylation. This IRF8 gene silencing may contribute to the malignancy of multiple myeloma.

Area of Science:

  • Hematology
  • Molecular Biology
  • Epigenetics

Background:

  • Multiple myeloma (MM) is an incurable plasma cell malignancy.
  • The interferon regulatory factor (IRF) family's role in MM is not fully understood.
  • Epigenetic modifications, such as DNA methylation, can regulate gene expression in cancer.

Purpose of the Study:

  • To investigate the expression of IRF family members (IRF1-9) in multiple myeloma.
  • To determine the role of DNA methylation in silencing IRF genes, particularly interferon consensus sequence-binding protein (ICSBP/IRF8), in MM.
  • To analyze the association between IRF8 gene silencing and the malignant phenotype of MM.

Main Methods:

  • Quantitative reverse transcriptase polymerase chain reaction and Western blot were used to assess IRF gene expression in 13 MM cell lines and primary MM cells.
  • Pyrosequencing analyzed DNA methylation of the ICSBP/IRF8 promoter.
  • In vitro methylation and 5-aza-2'-deoxycytidine (DAC) treatment were employed to study the effect of methylation on ICSBP/IRF8 expression.

Main Results:

  • ICSBP/IRF8 expression was absent in 8/13 MM cell lines, correlating with promoter hypermethylation.
  • ICSBP/IRF8 was significantly underexpressed in primary MM cells, with methylation present in only one sample.
  • DAC treatment restored ICSBP/IRF8 expression, while in vitro methylation silenced it.

Conclusions:

  • ICSBP/IRF8 gene expression is frequently silenced in multiple myeloma cell lines and primary cells.
  • DNA methylation is a common mechanism for ICSBP/IRF8 silencing in MM cell lines, but other epigenetic mechanisms also contribute.
  • Silencing of ICSBP/IRF8, via DNA methylation or other epigenetic means, may be linked to the malignant characteristics of multiple myeloma.

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