Читать книгу The Peripheral T-Cell Lymphomas - Группа авторов - Страница 75

Homozygous Tet2 gene trap(Tet2^gt/gt) mice harbor a gene‐trap vector in the Tet2 second intron [10]. Muto et al. reported that 70% of Tet2^gt/gt mice developed T‐cell lymphomas with Tfh‐like gene expression patterns around 67 weeks old [10]. DNA methylation analysis revealed that lymphoma cells of Tet2^gt/gt mice exhibited increased methylation at transcriptional start sites, gene bodies and CpG islands, and decreased hydroxymethylation at transcriptional start site regions [10]. Hypermethylation of the first intronic silencer region of the Bcl6 gene reportedly has been known to inhibit CCCTC‐binding factor (CTCF) binding to this locus and promotes Bcl6 transcription [11]. Density of methylation was increased in lymphoma cells of Tet2^gt/gt mice compared with control CD4+ cells [10]. Upregulation of Bcl6, encoding a master transcriptional regulator in Tfh development finally results in outgrowth of Tfh‐like cells in Tet2^gt/gt mice [10]. These results suggest overall that decreased Tet2 function contributes to AITL initiation. Notably, hypermethylation of the corresponding region in BCL6 locus is also found in human PTCL samples with TET2 mutations [12].