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

Blood | May 28, 2009

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 RIS Download

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

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Associated grants

  • Agency: NCI NIH HHS, Id: CA101956
  • Agency: NCI NIH HHS, Id: CA93548
  • Agency: NCI NIH HHS, Id: P01 CA101956
  • Agency: NCI NIH HHS, Id: R01 CA093548
  • Agency: NCI NIH HHS, Id: CA68458
  • Agency: NCI NIH HHS, Id: R01 CA068458
  • Agency: NCI NIH HHS, Id: P01 CA095426
  • Agency: NCI NIH HHS, Id: CA95426
  • Agency: NCI NIH HHS, Id: R37 CA068458

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