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Blood, 15 July 2008, Vol. 112, No. 2, pp. 383-393.
Prepublished online as a Blood First Edition Paper on May 8, 2008; DOI 10.1182/blood-2008-01-131185.
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Submitted January 7, 2008
Accepted April 4, 2008
Down-regulation of TCF8 is involved in the leukemogenesis of adult-T cell leukemia/lymphoma
Tomonori Hidaka, Shingo Nakahata, Kinta Hatakeyama, Makoto Hamasaki, Kiyoshi Yamashita, Takashi Kohno, Yasuhito Arai, Tomohiko Taki, Kazuhiro Nishida, Akihiko Okayama, Yujiro Asada, Ryoji Yamaguchi, Hirohito Tsubouchi, Jun Yokota, Masafumi Taniwaki, Yujiro Higashi, and Kazuhiro Morishita*
Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
First Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
Miyazaki Prefectural Industrial Foundation, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
Department of Internal Medicine II, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
Biology Division, National Cancer Center Research Institute, Tokyo, Japan
Cancer Genome Project, National Cancer Center Research Institute, Tokyo, Japan
Department of Hematology and Oncology, Kyoto Prefectural University of Medicine, Kyoto, Japan
Department of Rheumatology, Infectious Diseases and Laboratory Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
Department of Veterinary Pathology, University of Miyazaki, Miyazaki, Japan
Department of Digestive and Live-style related Disease, Kagoshima University Graduate School of Medicine and Dental Sciences, Kagoshima, Japan
Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
* Corresponding author; email: kmorishi{at}med.miyazaki-u.ac.jp.
Adult T-cell leukemia/lymphoma (ATLL) is caused by latent human T-lymphotropic virus-1 (HTLV-1) infection. To clarify the molecular mechanism underlying leukemogenesis after viral infection, we precisely mapped 605 chromosomal breakpoints in 61 ATLL cases by spectral karyotyping and identified frequent chromosomal breakpoints in 10p11, 14q11, and 14q32. Single nucleotide polymorphism (SNP) array-comparative genomic hybridization (CGH), genetic, and expression analyses of the genes mapped within a common breakpoint cluster region in 10p11.2 revealed that in ATLL cells, transcription factor 8 (TCF8) was frequently disrupted by several mechanisms, mainly including epigenetic dysregulation. TCF8-mutant mice frequently developed invasive CD4+ T-cell lymphomas in the thymus or in ascitic fluid in vivo. Down-regulation of TCF8 expression in ATLL cells in vitro was associated with resistance to transforming growth factor (TGF)- 1, a well-known characteristic of ATLL cells, suggesting that escape from TGF-1-mediated growth inhibition is important in the pathogenesis of ATLL. These findings indicate that TCF8 has a tumor suppressor role in ATLL.
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