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

Blood. 2009 May 28;113(22):5558-67. doi: 10.1182/blood-2009-02-205732.

Jianhua Yu ¹, 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

Affiliations

Affiliation

1 Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA. jianhua.yu@osumc.edu

PMID: 19329776 DOI: 10.1182/blood-2009-02-205732

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.

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