Loss of interleukin-2-dependency in HTLV-I-infected T cells on gene silencing of thioredoxin-binding protein-2

Oncogene. 2006 Apr 6;25(15):2181-91. doi: 10.1038/sj.onc.1209256.


The transition from interleukin-2 (IL-2)-dependent to IL-2-independent growth is considered one of the key steps in the transformation of human T-cell leukemia virus type-I (HTLV-I)-infected T cells. The expression of thioredoxin-binding protein-2 (TBP-2) is lost during the transition of HTLV-I-infected T-cell lines. Here, we analysed the mechanism of loss of TBP-2 expression and the role of TBP-2 in IL-2-dependent growth in the in vitro model to investigate multistep transformation of HTLV-I. CpGs in the TBP-2 gene are methylated in IL-2-independent but not in IL-2-dependent cells. Sequential treatment with 5-aza-2'-deoxycytidine and a histone deacetylase inhibitor augmented histone acetylation and TBP-2 expression, suggesting that loss of TBP-2 expression is due to DNA methylation and histone deacetylation. In IL-2-dependent cells, a basal level of TBP-2 expression was maintained by IL-2 associated with cellular growth, whereas TBP-2 expression was upregulated on deprivation of IL-2 associated with growth suppression. Overexpression of TBP-2 in IL-2-independent cells suppressed the growth and partially restored responsiveness to IL-2. Knockdown of TBP-2 caused the IL-2-dependent cells to show partial growth without IL-2. These results suggested that epigenetic silencing of the TBP-2 gene results in a loss of responsiveness to IL-2, contributing to uncontrolled IL-2-independent growth in HTLV-I-infected T-cell lines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Azacitidine / analogs & derivatives
  • Azacitidine / pharmacology
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cell Line, Tumor
  • Cell Transformation, Viral
  • Chromatin Immunoprecipitation
  • CpG Islands
  • DNA Methylation
  • DNA Modification Methylases / antagonists & inhibitors
  • Decitabine
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation, Viral
  • Gene Silencing*
  • Histone Deacetylase Inhibitors
  • Histones / metabolism
  • Human T-lymphotropic virus 1 / physiology*
  • Humans
  • Hydroxamic Acids / pharmacology
  • Interleukin-2 / genetics*
  • Interleukin-2 / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / virology*
  • Thioredoxins / genetics*
  • Thioredoxins / metabolism
  • Transcription, Genetic
  • Vorinostat


  • Carrier Proteins
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Histones
  • Hydroxamic Acids
  • Interleukin-2
  • RNA, Messenger
  • TXNIP protein, human
  • Thioredoxins
  • Vorinostat
  • Decitabine
  • DNA Modification Methylases
  • Azacitidine