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Journal of Virology, May 2004, p. 4582-4590, Vol. 78, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.9.4582-4590.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Apoptosis Induced by the Histone Deacetylase Inhibitor FR901228 in Human T-Cell Leukemia Virus Type 1-Infected T-Cell Lines and Primary Adult T-Cell Leukemia Cells

Naoki Mori,1* Takehiro Matsuda,1,2 Masayuki Tadano,1 Takao Kinjo,3 Yasuaki Yamada,4 Kunihiro Tsukasaki,5 Shuichi Ikeda,6 Yoshihiro Yamasaki,7 Yuetsu Tanaka,8 Takao Ohta,2 Teruo Iwamasa,3 Masao Tomonaga,5 and Naoki Yamamoto9

Division of Molecular Virology and Oncology, Graduate School of Medicine,1 Divisions of Child Health and Welfare,2 Pathology and Cell Biology,3 Immunology, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa 903-0215,8 Division of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8501,4 Department of Hematology, Molecular Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, Nagasaki 852-8523,5 Department of Hematology, Sasebo City General Hospital, Sasebo 857-8511,6 Department of Internal Medicine, Kokura Memorial Hospital, Kitakyushu 802-8555,7 Department of Molecular Virology, Bio-Response, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8519, Japan9

Received 21 July 2003/ Accepted 28 January 2004

Inhibition of histone deacetylase (HDAC) activity induces growth arrest, differentiation, and, in certain cell types, apoptosis. FR901228, FK228, or depsipeptide, is an HDAC inhibitor effective in T-cell lymphomas. Adult T-cell leukemia (ATL) is caused by human T-cell leukemia virus type 1 (HTLV-1) and remains incurable. We examined whether FR901228 is effective for treatment of ATL by assessing its ability to induce apoptosis of HTLV-1-infected T-cell lines and primary leukemic cells from ATL patients. FR901228 induced apoptosis of Tax-expressing and -unexpressing HTLV-1-infected T-cell lines and selective apoptosis of primary ATL cells, especially those of patients with acute ATL. FR901228 also efficiently reduced the DNA binding of NF-{kappa}B and AP-1 in HTLV-1-infected T-cell lines and primary ATL cells and down-regulated the expression of Bcl-xL and cyclin D2, regulated by NF-{kappa}B. Although the viral protein Tax is an activator of NF-{kappa}B and AP-1, FR901228-induced apoptosis was not associated with reduced expression of Tax. In vivo use of FR901228 partly inhibited the growth of tumors of HTLV-1-infected T cells transplanted subcutaneously in SCID mice. Our results indicated that FR901228 could induce apoptosis of these cells and suppress the expression of NF-{kappa}B and AP-1 and suggest that FR901228 could be therapeutically effective in ATL.

* Corresponding author. Mailing address: Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan. Phone: 81 (98) 895-1130. Fax: 81 (98) 895-1410. E-mail: n-mori{at}med.u-ryukyu.ac.jp.

Journal of Virology, May 2004, p. 4582-4590, Vol. 78, No. 9
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.9.4582-4590.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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