Molecular mechanism of leukemogenesis in ATL

• Project/Area Number: 17013046
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Kyoto University
• Principal Investigator: MATSUOKA Masao Kyoto University, ウイルス研究所, 教授 (10244138)
• Project Period (FY): 2005 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥53,500,000 (Direct Cost: ¥53,500,000); Fiscal Year 2009: ¥10,700,000 (Direct Cost: ¥10,700,000); Fiscal Year 2008: ¥10,700,000 (Direct Cost: ¥10,700,000); Fiscal Year 2007: ¥10,700,000 (Direct Cost: ¥10,700,000); Fiscal Year 2006: ¥10,700,000 (Direct Cost: ¥10,700,000); Fiscal Year 2005: ¥10,700,000 (Direct Cost: ¥10,700,000)
• Keywords: ヒトT細胞白血病ウイルス1型 / 成人T細胞白血病 / ウイルス発がん / HBZ / Tax / レトロウイルス / 発がん / ヒトT細胞白血病ウイルス / がんウイルス / tax / RNA / DNAメチル化

Research Abstract

Analyses of HTLV-1 provirus in ATL cases showed that Tax was not expressed in about 60% of cases. Nonsense mutations in HTLV-1 provirus of ATL cases were found in all viral genes except HBZ gene, and generated by APOBEC3G before integration. In addition, deletion of 5'LTR of HTLV-1 provirus in ATL cases also occurred before integration. These findings suggest significance of HBZ gene in ATL cases. The HBZ gene transcript was found in all ATL cases, and had growth-promoting activity. In HBZ transgenic mice, T-cell lymphomas and inflammatory diseases occurred, indicating that HBZ gene plays a central role in the pathogenesis by HTLV-1.

Research Products

• [Journal Article] Human T-cell leukemia virus type 1 bZIP factor selectively suppresses the classical pathway of NF-kB. (2009)
  • Author(s): Zhao T, Yasunaga J-I, Satou Y, Nakao M, Takahashi M, Fujii M, Matsuoka M.
  • Journal Title: Blood 113 Pages: 2755-2764
  • Peer Reviewed
• [Journal Article] Human T-cell leukemia virus type 1 bZIP factor selectively suppresses the classical pathway of NF-kB. (2009)
  • Author(s): Zhao T
  • Journal Title: Blood 113 Pages: 2755-2764
  • Peer Reviewed
• [Journal Article] SKI and MEL 1 cooperate to inhibit transforming growth factor-β signal in gastric cancer cells. (2009)
  • Author(s): Takahata M
  • Journal Title: J Biol Chem 284 Pages: 3334-3344
  • Peer Reviewed
• [Journal Article] In vivo expression of the HBZ gene of HTLV-1 correlates with proviralload, inflammatory markers and disease severity in HTLV-1 associated myelopathy/tropical spastic paraparesis (HAMITSP) (2009)
  • Author(s): Saito M
  • Journal Title: Retrovirology 6 Pages: 19-19
  • Peer Reviewed
• [Journal Article] Multi-step aberrant CpG island hyper-methylation is associated with the progression of adult T-cell leukemia/lymphoma (ATLL) (2009)
  • Author(s): Sato H
  • Journal Title: J Gen Virol 176 Pages: 402-415
  • Peer Reviewed
• [Journal Article] HBZ is an immunogenic protein, but not a target antigen for human T-cell leukemia virus type 1-specific cytotoxic T lymphocytes. (2009)
  • Author(s): Suemori K
  • Journal Title: 90 Pages: 1806-1811
  • Peer Reviewed
• [Journal Article] Transcriptional control of spliced and unspliced HTLV-1 bZIP factor gene. (2008)
  • Author(s): Yoshida M, Satou Y, Yasunaga J-I, Fujisawa JI, Matsuoka M.
  • Journal Title: J Virol 82 Pages: 9359-9368
  • Peer Reviewed
• [Journal Article] Broad Anti-Retroviral Activity and Resistance Profile of a Novel Human Immunodeficiency Virus Integrase Inhibitor, Elvitegravir (JTK-303/GS-9137) (2008)
  • Author(s): Shimura K.
  • Journal Title: J Virol. 82 Pages: 764-774
  • Peer Reviewed
• [Journal Article] Adult T-cell leukemia/lymphoma ; Hematopoietic stem cell transplantation ; allogeneic ; reducedintensity transplantation ; anti-thymocyte globulin ; graft-versus-ATLL effect (2008)
  • Author(s): Tanosaki R.
  • Journal Title: Biology of Blood and Marrow Transplantation 14 Pages: 702-708
  • Peer Reviewed
• [Journal Article] A Potential link between alternative splicing of the NBS1 gene and the DNAdamage/environmental stress (2008)
  • Author(s): Takai K.
  • Journal Title: Radiation Res 170 Pages: 33-40
  • Peer Reviewed
• [Journal Article] Transcriptional control of spliced and unspliced HTLV-1 bZIP factor gene (2008)
  • Author(s): Yoshida M.
  • Journal Title: J Virol 82 Pages: 9359-9368
  • Peer Reviewed
• [Journal Article] Roles for microRNAs, miR-93 and miR-130b, and TP53INP1 tumor suppressor in cell growth dysregulation by HTLV-1 (2008)
  • Author(s): Yeung ML.
  • Journal Title: Cancer Res 68 Pages: 8976-8985
  • Peer Reviewed
• [Journal Article] Broad Anti-Retroviral Activity and Resistance Profile of a Novel Human Immunodeficiency Virus Integrase Inhibitor, Elvitegravir (JTK-303/GS-9137). (2008)
  • Author(s): Shimura K.
  • Journal Title: J Virol. 82 Pages: 764-774
  • Peer Reviewed
• [Journal Article] A Dual-Reporter Phenotypic Assay for Human Immunodeficiency Viruses. (2008)
  • Author(s): Kajiwara K.
  • Journal Title: J Clin Microbiol. 46 Pages: 792-795
  • Peer Reviewed
• [Journal Article] Human T-cell leukemia virus type 1 (HTLV-1) infectivity and cellular transformation. (2007)
  • Author(s): Matsuoka M., Jeang KT.
  • Journal Title: Nat Rev Cancer 7 Pages: 270-280
  • Peer Reviewed
• [Journal Article] Preferential Selection of HTLV-1 Provirus Lacking the 5'LTR during Oncogenesis. (2007)
  • Author(s): Miyazaki M, Yasunaga J-I, Taniguchi Y, Tamiya S, Nakahata T, Matsuoka M.
  • Journal Title: J Virol 81 Pages: 5714-5723
  • Peer Reviewed
• [Journal Article] Phenotypic and genotypic comparison of human T-cell leukemia virus type 1 reverse transcriptase from infected T-cell lines and patient samples. (2007)
  • Author(s): Mitchell MS.
  • Journal Title: J Virol. 81 Pages: 4422-4428
  • Peer Reviewed
• [Journal Article] Preferential Selection of HTLV-1 Provirus Lacking the 5'LTR during Oncogenesis. (2007)
  • Author(s): Miyazaki M.
  • Journal Title: J Virol. 81 Pages: 5714-5723
  • Peer Reviewed
• [Journal Article] Antiviral Activity against HIV-1, Intracellular Metabolism, and Effects on Human DNA Polymerases of 4'-Ethynyl-2-fluoro-2'-deoxyadenosine. (2007)
  • Author(s): Nakata H.
  • Journal Title: Antimicrob. Agents Chemother. 51 Pages: 2701-2708
  • Peer Reviewed
• [Journal Article] Development of adult T-cell leukemia in donor-derived human T-cell leukemia virus type I-infected T cells after allogeneic bone marrow transplantation. (2007)
  • Author(s): Tamaki H.
  • Journal Title: Leukemia 21 Pages: 1594-1596
  • Peer Reviewed
• [Journal Article] Cooperation of NF-_κB2/p100 activation and the PDZ domain binding motif signal in human T-cell leukemia virus type 1 (HTLV) Taxl but not HTLV-2 Tax2 is crucial for interleukin-2 independent growth transformation of a T cell line. (2007)
  • Author(s): Higuchi M
  • Journal Title: J Virol. 81 Pages: 11900-11907
  • Peer Reviewed
• [Journal Article] GANP suppresses DNA recombination, measured by direct-repeat beta-galactosidase gene construct, but does not suppress the type of recombination applying to immunoglobulin genes in mammalian cells. (2007)
  • Author(s): Yoshida M.
  • Journal Title: Genes Cells 12 Pages: 1205-1213
  • Peer Reviewed
• [Journal Article] Heptad repeat-derived peptides block the protease-mediated direct entry from cell surface of SARS coronavirus but not entry via endosomal pathway. (2007)
  • Author(s): Ujike M.
  • Journal Title: J Virol. 82 Pages: 588-592
  • Peer Reviewed
• [Journal Article] The HTLV- I bZIP factor gene mRNA supports proliferation of adult T-cell leukemia cells. (2006)
  • Author(s): Satou Y, Yasunaga J-I, Yoshida M, Matsuoka M.
  • Journal Title: Proc Natl Acad Sci USA 103 Pages: 720-725
  • Peer Reviewed
• [Journal Article] Donor-derived adult T-cell leukemia after allogeneic bone marrow transplantation. (2006)
  • Author(s): Tamaki H, Matsuoka M.
  • Journal Title: N Eng J Med 354 Pages: 1758-1759
  • Peer Reviewed
• [Journal Article] De novo Human T-Cell Leukemia Virus Type 1 infection of human lymphocytes in NOD-SCID, common g-chain knockout mice. (2006)
  • Author(s): Miyazato P, Yasunaga J-I, Taniguchi Y, Koyanagi Y, Mitsuya H, Matsuoka M.
  • Journal Title: J Virol 80 Pages: 10683-10691
  • Peer Reviewed
• [Journal Article] HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells. (2006)
  • Author(s): Satou Y.
  • Journal Title: Proc.Natl.Acad.Sci.USA. 103 Pages: 720-725
• [Journal Article] De Novo Human T-Cell Leukemia Virus Type 1 Infection of Human Lymphocytes in NOD-SCID, Common γ-Chain Knockout Mice. (2006)
  • Author(s): Miyazato P.
  • Journal Title: J Virol. 80 Pages: 10683-10691
• [Journal Article] Donor-Derived T-cell leukemia after Bone Marrow Transplantation. (2006)
  • Author(s): Tamaki H.
  • Journal Title: N Engl J Med. 354(16) Pages: 1758-1759
• [Journal Article] Loss of interleukin-2-dependency in HTLV-I-infected T-cells on gene silencing of thioredoxin-binding protein-2. (2006)
  • Author(s): Ahsan MK.
  • Journal Title: Oncogene 25 Pages: 2181-2191
• [Journal Article] Sea Urchin Arylsulfatase Insulator Exerts its Anti-silencing Effect without Interacting with the Nuclear Matrix. (2006)
  • Author(s): Hino S.
  • Journal Title: J.Mol.Biol. 357 Pages: 18-27
• [Journal Article] Ars Insulator Identified in Sea Urchin Possesses an Activity to Ensure the Transgene Expression in Mouse Cells. (2006)
  • Author(s): Tajima S.
  • Journal Title: J Biochem 139(4) Pages: 705-714
• [Journal Article] HTLV-I basic leucine zipper factor gene mRNA supports proliferation of adult T cell leukemia cells. (2006)
  • Author(s): Satou Y.
  • Journal Title: Proc.Natl.Acad.Sci.USA 103 Pages: 720-725
• [Journal Article] Silencing of human T-cell leukemia virus type I gene transcription by epigenetic mechanisms. (2005)
  • Author(s): Taniguchi Y.
  • Journal Title: Retrovirology 2 Pages: 64-64
• [Journal Article] Preferential selection of human T-cell leukemia virus type I (HTLV-I) provirus integration sites in leukemic versus carrier states. (2005)
  • Author(s): Doi K.
  • Journal Title: Blood 106 Pages: 1048-1053
• [Journal Article] Halogenated thymidine analogs restore the expression of silenced genes without demethylation. (2005)
  • Author(s): Fan J.
  • Journal Title: Cancer Res 65 Pages: 6927-6933
• [Journal Article] Human T-cell leukemia virus type I (HTLV-I) infection and the onset of adult T-cell leukemia (ATL). (2005)
  • Author(s): Matsuoka M.
  • Journal Title: Retrovirology 2 Pages: 27-27
  • NAID: 120004754360
• [Journal Article] Human T-cell leukemia virus type I at age 25 : a progress report. (2005)
  • Author(s): Matsuoka M.
  • Journal Title: Cancer Res 65 Pages: 4467-4470
• [Journal Article] Natural history of adult T-cell leukemia/lymphoma and approaches to therapy. (2005)
  • Author(s): Taylor G P.
  • Journal Title: Oncogene 24 Pages: 6047-6057
• [Presentation] ヒトT細胞白血病ウイルスによる病原性発現機構 (2009)
  • Author(s): 松岡雅雄
  • Organizer: 第7回HAM治療研究会
  • Place of Presentation: グランヴィア大阪(大阪府大阪市)
  • Year and Date: 2009-07-31
• [Presentation] The Roles of HTLV-1 bZIP Factor Gene in Oncogenesis. (2009)
  • Author(s): Matsuoka M.
  • Organizer: The 14th International Conference on Human Retrovirology:HTLV and related retroviruses.
  • Place of Presentation: Salvador, Brazil
• [Presentation] The Roles of HTLV-1 bZIP Factor Gene in Oncogenesis. (2009)
  • Author(s): Matsuoka M
  • Organizer: The 14^<th> Intemational Conference on Human Retrovirology : HTLV and related retroviruses.
  • Place of Presentation: Salvador, Brazil
• [Presentation] HTLV-1 bZIP factor selectively suppresses the classical pathway of NF-kB. (2009)
  • Author(s): Zhao T
  • Organizer: The 16^<th> East Asia Joint Conference on Biomedical Research.
  • Place of Presentation: Shirankaikan, Kyoto, Japan
• [Presentation] ヒトT細胞白血病ウイルス1型の病原性発現機構 (2009)
  • Author(s): 松岡雅雄
  • Organizer: 第49回日本リンパ網内系学会総会
  • Place of Presentation: 淡路夢舞台国際会議場(兵庫県淡路市)
• [Presentation] ATF3はHTLV-1 bZIP factorと相互作用し、ATL細胞の増殖に寄与する (2009)
  • Author(s): 萩屋啓太
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川県横浜市)
• [Presentation] Molecular pathogenesis and host immune response (2008)
  • Author(s): Matsuoka M.
  • Organizer: IID 2008 Satellite Workshop "Virus-associated Lymphomas"
  • Place of Presentation: Kyoto, Japan.(京都国際会館)
  • Year and Date: 2008-05-13
• [Presentation] Lentivirus integration and DNA repair (2008)
  • Author(s): Matsuoka M.
  • Organizer: Ataxia-Telangiectasia Workshop 2008
  • Place of Presentation: Otsu, Japan.(大津プリンスホテル)
  • Year and Date: 2008-04-22
• [Presentation] HTLV-I bZIP fctor(HBZ)によるT細胞増殖促進の分子機構 (2007)
  • Author(s): 安永純一朗
  • Organizer: 第30回日本分子生物学会年会・第80回日本生化学会大会合同大会
  • Place of Presentation: 横浜(パシフィコ横浜)
  • Year and Date: 2007-12-15
• [Presentation] Molecular mechanism of pathogenesis by human T-cell leukemia virus type I (2007)
  • Author(s): 松岡雅雄
  • Organizer: 第12回慶應医学賞記念シンポジウム
  • Place of Presentation: 東京(慶応大学)
  • Year and Date: 2007-12-05
• [Presentation] 欠損型プロウイルスの解析からみた発がんにおけるHTLV-I bZIP factorの重要性 (2007)
  • Author(s): 安永純一朗
  • Organizer: \9回日本血液学会総会・第49回日本臨床血液学会総会
  • Place of Presentation: 横浜(パシフィコ横浜)
  • Year and Date: 2007-10-11
• [Presentation] Leukemogenesis associated with HTLV-I bZIP factor gene in ATL (2007)
  • Author(s): 松岡雅雄
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜(パシフィコ横浜)
  • Year and Date: 2007-10-03
• [Presentation] HTLV-I bZIP factor suppresses canonical pathway of NF-κB by physical interaction with the p65. (2007)
  • Author(s): 趙鉄軍
  • Organizer: 第66回日本癌学会学術総会
  • Place of Presentation: 横浜(パシフィコ横浜)
  • Year and Date: 2007-10-03
• [Presentation] HTLV-I bZIP Facotr Gene and Oncogenesis by HTLV-I. (2007)
  • Author(s): Matsuoka M.
  • Organizer: The 13th International Conference on Human Retrovirology.
  • Place of Presentation: Hakone, Japan.(箱根プリンスホテル)
  • Year and Date: 2007-05-22
• [Presentation] HBZ transgenic mice mimic skin and lung diseases associated with HTLV-I (2007)
  • Author(s): Satou Y.
  • Organizer: The 13th International Conference on Human Retrovirology.
  • Place of Presentation: Hakone, Japan.(箱根プリンスホテル)
  • Year and Date: 2007-05-22
• [Presentation] Characterization of the promoter region for HBZ gene and functional analyses of spliced and unspliced HBZ genes. The 13th International Conference on Human Retrovirology. (2007)
  • Author(s): Yoshida M.
  • Organizer: The 13th International Conference on Human Retrovirology.
  • Place of Presentation: Hakone, Japan.(箱根プリンスホテル)
  • Year and Date: 2007-05-22
• [Presentation] HTLV-I bZIP Facotr Gene and Oncogenesis by HTLV-I. (2007)
  • Author(s): Matsuoka M.
  • Organizer: The 13th International Conference on Human Retrovirology.
  • Place of Presentation: Hakone, Japan.
• [Presentation] Molecular mechanisms of leukemogenesis in HTLV-1 induced adult T-cell leukemia. (2006)
  • Author(s): Matsuoka M.
  • Organizer: THE 19TH INTERNATIONAL SYPOSIUM Infection, Cancer and Prevention.
  • Place of Presentation: Tokyo, Japan
• [Presentation] Molecular mechanism of leukemogenesis from HTLV-I infection to onset of ATL. (2005)
  • Author(s): Matsuoka M.
  • Organizer: The 12th International Conference on Human Retrovirology.
  • Place of Presentation: Montego Bay, Jamaica.
• [Book] The Lymphoma, 2nd ed.(Edited by Canellos, G.P., Lister, T.A., Young, B., Human T-cell leukemia virus type I.) (2006)
  • Author(s): Matsuoka M.
• [Book] The Lymphomas SECOND EDITION. (2006)
  • Author(s): Matsuoka M.
  • Total Pages: 12