title: TSC-22 contributes to hematopoietic precursor cell proliferation and repopulation and is epigenetically silenced in large granular lymphocyte leukemia.
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.
authors.affiliation: Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA. jianhua.yu@osumc.edu
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
authors.forename: Maxim
authors.initials: M
authors.lastname: Ershler
authors.forename: Li
authors.initials: L
authors.lastname: Yu
authors.forename: Min
authors.initials: M
authors.lastname: Wei
authors.forename: Björn
authors.initials: B
authors.lastname: Hackanson
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yokohama
authors.forename: Takeki
authors.initials: T
authors.lastname: Mitsui
authors.forename: Chunhui
authors.initials: C
authors.lastname: Liu
authors.forename: Hsiaoyin
authors.initials: H
authors.lastname: Mao
authors.forename: Shujun
authors.initials: S
authors.lastname: Liu
authors.forename: Zhongfa
authors.initials: Z
authors.lastname: Liu
authors.forename: Rossana
authors.initials: R
authors.lastname: Trotta
authors.forename: Chang-gong
authors.initials: CG
authors.lastname: Liu
authors.forename: Xiuping
authors.initials: X
authors.lastname: Liu
authors.forename: Kun
authors.initials: K
authors.lastname: Huang
authors.forename: Jan
authors.initials: J
authors.lastname: Visser
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Belyavsky
authors.forename: Michael A
authors.initials: MA
authors.lastname: Caligiuri