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

Jianhua Yu, Maxim Ershler, Li Yu, Min Wei, Björn Hackanson, Akihiko Yokohama, Takeki Mitsui, Chunhui Liu, Hsiaoyin Mao, Shujun Liu, Zhongfa Liu, Rossana Trotta, Chang Gong Liu, Xiuping Liu, Kun Huang, Jan Visser, Guido Marcucci, Christoph Plass, Alexander V. Belyavsky, Michael A. Caligiuri

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5558-5567
Number of pages10
JournalBlood
Volume113
Issue number22
DOIs
StatePublished - 2009
Externally publishedYes

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