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TSC-22 contributes to hematopoietic precursor cell proliferation and repopulation and is epigenetically silenced in large granular lymphocyte leukemia.

Aberrant methylation of tumor suppressor genes can lead to their silencing in many cancers. TSC-22 is a gene silenced in several solid tumors, but its function and the mechanism(s) responsible for its silencing are largely unknown. Here we demonstrate that the TSC-22 promoter is methylated in primary mouse T or natural killer (NK) large granular lymphocyte (LGL) leukemia and this is associated with down-regulation or silencing of TSC-22 expression. The TSC-22 deregulation was reversed in vivo by a 5-aza-2'-deoxycytidine therapy of T or NK LGL leukemia, which significantly increased survival of the mice bearing this disease. Ectopic expression of TSC-22 in mouse leukemia or lymphoma cell lines resulted in delayed in vivo tumor formation. Targeted disruption of TSC-22 in wild-type mice enhanced proliferation and in vivo repopulation efficiency of hematopoietic precursor cells (HPCs). Collectively, our data suggest that TSC-22 normally contributes to the regulation of HPC function and is a putative tumor suppressor gene that is hypermethylated and silenced in T or NK LGL leukemia.

Pubmed ID: 19329776

Authors

  • Yu J
  • Ershler M
  • Yu L
  • Wei M
  • Hackanson B
  • Yokohama A
  • Mitsui T
  • Liu C
  • Mao H
  • Liu S
  • Liu Z
  • Trotta R
  • Liu CG
  • Liu X
  • Huang K
  • Visser J
  • Marcucci G
  • Plass C
  • Belyavsky AV
  • Caligiuri MA

Journal

Blood

Publication Data

May 28, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: CA101956
  • Agency: NCI NIH HHS, Id: CA68458
  • Agency: NCI NIH HHS, Id: CA93548
  • Agency: NCI NIH HHS, Id: CA95426

Mesh Terms

  • Animals
  • Cell Movement
  • Cell Proliferation
  • Cells, Cultured
  • DNA Methylation
  • Epigenesis, Genetic
  • Gene Expression Regulation, Leukemic
  • Gene Silencing
  • Genes, Tumor Suppressor
  • Hematopoietic Stem Cells
  • Humans
  • Leukemia, Large Granular Lymphocytic
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Promoter Regions, Genetic
  • Repressor Proteins