演題詳細

一般口演 / Oral Session

【E】一般口演 13 (Oral Session 13) :Malignant Lymphoma:Genomic Alteration

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日程
2013年10月11日(金)
時間
09:30 - 10:30
会場
第9会場 / Room No.9 (ロイトン札幌 1F キャッスル)
座長・司会
渡邊 俊樹 (Toshiki Watanabe):1
1:Laboratory of Tumor Cell Biology, Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Japan
 
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Bcl6 is hypermethylated in lymphomas developed in Tet2 knockdown mice

演題番号 : OS-1-61

武藤 秀治 (Hideharu Muto):1、坂田 麻実子 (Mamiko Sakata-Yanagimoto):1、三宅 康行 (Yasuyuki Miyake):1、榎並 輝和 (Terukazu Enami):1、鎌田 勇平 (Yuhei Kamada):1、鈴川 和己 (Kazumi Suzukawa):1、中村 直哉 (Naoya Nakamura):2、永江 玄太 (Genta Nagae):3、油谷 浩幸 (Hiroyuki Aburatani):3、小川 誠司 (Seishi Ogawa):4、千葉 滋 (Shigeru Chiba):1

1:Department of Hematology, University of Tsukuba, Japan、2:Department of Pathology, Tokai University School of Medicine, Japan、3:Genome Science Division RCAST- The University of Tokyo, Japan、4:Cancer Genomics Project, Graduate School of Medicine, The University of Tokyo, Japan

 

Background: Loss-of-function mutations in TET2 are frequent in subtypes of T-cell lymphomas, as well as myeloid malignancies. In the last annual meeting, we reported that Tet2 gene trap (Tet2gt) mice developed peripheral T-cell lymphoma (PTCL) after a long latency (unpublished data). To investigate the downstream mechanism of lymphomagenesis, we performed cDNA microarray and DNA methylation. Methods: Tet2 gt mice have a trapping vector inserted into the second intron of Tet2 locus. Gene Set Enrichment Analysis (GSEA) was performed with two sets of gene expression data obtained from CD4+ cells of lymphoma tissues and control mice spleen. MeDIP sequencing was performed followed by validation by bisulfite sequencing. Results: After an observation over a year (median, 67 weeks), 5 out of 7 Tet2gt/gt mice developed overt lymphomas. Lymphoma cells were positive for CD4/PD1/Cxcr5, and thus showed a phenotype of follicular helper T cells (Tfh). GSEA analysis of lymphoma cells revealed upregulation of Tfh-associated genes such as Bcl6 and cMaf, key transcription factors of Tfh cells. It is already known that hypermethylation at an intron1 of Bcl6 upregulates its transcriptional activity in B cell lymphomas. MeDIP and bisulfite sequencing analyses revealed that CpG islands at intron1 of Bcl6 were hypermethylated in the lymphoma cells. Conclusion: Hypermethylation of Bcl6 and an increase of Bcl6 expression were observed in CD4+ T cells of Tet2 gt/gt mice. Epigenetic dysregulation of Bcl6 due to Tet2 impairment might have important roles for T-lymphomagenesis.

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