Journal
BLOOD
Volume 113, Issue 22, Pages 5558-5567Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-02-205732
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Funding
- National Cancer Institute [CA95426, CA68458, CA93548, CA101956]
- Division of Human Cancer Genetics at The Ohio State University (J.Y.),
- Dr Mildred Scheel Foundation for Cancer Research (B.H.)
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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. (Blood. 2009; 113: 5558-5567)
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