Analyzing the mechanisms underlying ATL leukemogenesis and identifying new markers of ATL stem cell using ATL humanized mice

• Project/Area Number: 24591383
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: The University of Tokyo
• Principal Investigator: YAMOCHI Tadanori 東京大学, 新領域創成科学研究科, 特任研究員 (80306844)
• Co-Investigator(Kenkyū-buntansha): WATANABE Nobukazu 九州がんセンター, 細胞治療科, 医長 (10334278)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: Adult T cell leukemia / Cancer stem cells / Tumor initiating cells / ATL / Adult T cell Leukemia / Cancer stem cell / 癌幹細胞 / 成人T細胞性白血病

Outline of Final Research Achievements

We have been searching for cancer stem cells (CSCs) of adult T cell leukemia (ATL). We have defined CSCs in the tumor as tumorigenic cells capable of dividing into tumorigenic cells and non-tumorigenic cells, which can be distinguished based on their cell surface markers and serial transplantablity in immunodeficient mice. We successfully established a number of serially transplanted cell lines by intra-liver transplantation of PBMC from ATL patients into NOJ mice. One of the cell lines, derived from CD4+ CCR4+ sorted cells showed ATL-like phenotypes such as the infiltration into spleen, liver, lung and born marrow, and the surface markers of CD4+, CCR4+, CD5+, cytoplasmic CD3+ and surface CD3-. This cell line harbored complicated chromosomal abnormalities including t (11, 14) translocation and a partial trisomy of chromosome 14. We have identified candidate markers that can discriminate the tumorigenic cells from non-tumorigenic cells in the CD4+ CCR4+ transplanted cell line.

Research Products

• [Journal Article] Advanced HTLV-1 carriers and early-stage indolent ATLs are indistinguishable based on CADM1 positivity in flow cytometry (2015)
  • Author(s): Kobayashi S, Watanabe E, Ishigaki T, Ohno N, Yuji K, Nakano K, Yamochi T, Watanabe N, Tojo A, Watanabe T, Uchimaru K.
  • Journal Title: Cancer Sci Volume: 印刷中 Issue: 5 Pages: 598-603
  • DOI: 10.1111/cas.12639
  • Peer Reviewed / Open Access
• [Journal Article] Identification of TL-Om1, an ATL Cell Line, as a Reference Material for Human T-Lymphotropic Virus 1 Quantitative PCR. (2015)
  • Author(s): Kuramitsu M, Okuma K, Yamagishi M, Yamochi T, Firouzi S, Momose H, Mizukami T, Takizawa K, Araki K, Sugamura K, Yamaguchi K, Watanabe T, Hamaguchi I.
  • Journal Title: Journal of Clinical Microbiology Volume: 53 Issue: 2 Pages: 587-596
  • DOI: 10.1128/jcm.02254-14
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Clinical outcomes of a novel therapeutic vaccine with Tax peptide-pulsed dendritic cells for adult T-cell leukemia/lymphoma in a pilot study. (2015)
  • Author(s): Suehiro Y, Atsuhiko Hasegawa A, Tadafumi Iino T, Amane Sasada A, Nobukazu Watanabe N, Masao Matsuoka M, Ayako Takamori A, Ryuji Tanosaki R, Atae Utsunomiya A, Ilseung Choi I, Tetsuya Fukuda T, Osamu Miura O, Shigeo Takaishi S, Takanori Teshima T, Koichi Akashi K, Mari Kannagi M, Naokuni Uike N, Jun Okamura J
  • Journal Title: Br J Haematol Volume: 169 Issue: 3 Pages: 356-367
  • DOI: 10.1111/bjh.13302
  • Peer Reviewed
• [Journal Article] Quantification of adult T-cell leukemia/lymphoma cells using simple four-color flow cytometry (2015)
  • Author(s): Ishigaki T, Zaike Y, Nojima M, Kobayashi S, Ohno N, Uchimaru K, Tojo A, Nakauchi H, Watanabe N
  • Journal Title: Clinical Chemistry and Laboratory Medicine Volume: 53(1) Issue: 1 Pages: 85-93
  • DOI: 10.1515/cclm-2014-0183
  • Peer Reviewed
• [Journal Article] HTLV-1キャリアが産生するウイルス構造蛋白質に対する抗体と末梢血中のプロウイルス量に関する解析」、 (2014)
  • Author(s): 井上由紀子，守田麻衣子，後藤信代，相良康子，入田和男，矢持忠徳，渡邉俊樹，岩永正子，浜口功，清川博之、
  • Journal Title: 日本輸血細胞治療学会誌 Volume: 60(6) Pages: 592-599
  • Peer Reviewed
• [Journal Article] Epigenetic deregulation of Ellis Van Creveld confers robust Hedgehog signaling in adult T-cell leukemia (2014)
  • Author(s): Takahashi R; Yamagishi M, Nakano K, Yamochi T, Yamochi T, Fujikawa D, Nakashima M, Tanaka Y, Uchimaru K, Utsunomiya A, Watanabe T
  • Journal Title: Cancer Sci Volume: 105 Issue: 9 Pages: 1160-1169
  • DOI: 10.1111/cas.12480
  • Peer Reviewed / Open Access
• [Journal Article] Development and validation of a new high-throughput method to investigate the clonality of HTLV-1-infected cells based on provirus integration sites. (2014)
  • Author(s): Firouzi S, Lopez Y, Suzuki Y, Nakai K, Sugano S, Yamochi T, Watanabe T.
  • Journal Title: Genome Medicine Volume: 6(6) Issue: 6 Pages: 46-46
  • DOI: 10.1186/gm568
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] CADM1 expression and stepwise downregulation of CD7 are closely associated with clonal expansion of HTLV-I-infected cells in adult T-cell leukemia/lymphoma (2014)
  • Author(s): Kobayashi S, Nakano K, Watanabe E, Ishigaki T, Ohno N, Yuji K, Oyaizu N, Asanuma S, Yamagishi M, Yamochi T, Watanabe N, Tojo A, Watanabe T, Uchimaru K
  • Journal Title: Clinical Cancer Research Volume: 20(11) Issue: 11 Pages: 2851-61
  • DOI: 10.1158/1078-0432.ccr-13-3169
  • Peer Reviewed / Open Access
• [Journal Article] CADM1 expression and stepwise downregulation of CD7 are closely associated with 2 clonal expansion of HTLV-1-infected cells in adult T-cell leukemia/lymphoma (2014)
  • Author(s): Seiichiro Kobayashi, Kazumi Nakano, Eri Watanabe, Tomohiro Ishigaki, Nobuhiro Ohno, Koichiro Yuji, Naoki Oyaizu, Satomi Asanuma, Makoto Yamagishi, Tadanori Yamochi, Nobukazu Watanabe, Arinobu Tojo, Toshiki Watanabe, Kaoru Uchimaru
  • Journal Title: Clinical Cancer Research Volume: In Press
  • Peer Reviewed
• [Journal Article] Adult T-cell leukemia cells are characterized by abnormalities of Helios expression that promote T-cell growth. (2013)
  • Author(s): Asanuma S, Uchimaru K, et al.
  • Journal Title: Cancer Sci Volume: - Issue: 8 Pages: 1097-1106
  • DOI: 10.1111/cas.12181
  • Peer Reviewed
• [Journal Article] Adult T-cell leukemia cells are characterized by abnormalities of Helios expression that promotes T-cell growth. (2013)
  • Author(s): Asanuma S, Yamagishi M, Kawanami K, Nakano K, Sato-Otsubo A, Muto S, Sanada M, Yamochi T, Kobayashi S, Utsunomiya A, Iwanaga M, Yamaguchi K, Uchimaru K, Ogawa S, Watanabe T.
  • Journal Title: Cancer Science Volume: in press
  • Peer Reviewed
• [Journal Article] HIV-1-encoded antisense RNA suppresses viral replication for a prolonged period. (2012)
  • Author(s): Kobayashi-Ishihara M, Yamagishi M, Hara T, Matsuda Y, Takahashi R, Miyake A, Nakano K, Yamochi T, Ishida T, Watanabe T
  • Journal Title: Retrovirology Volume: 9 Issue: 1 Pages: 38-38
  • DOI: 10.1186/1742-4690-9-38
  • Peer Reviewed
• [Presentation] Monitoring clonal composition of HTLV-1-infected cells based on provirus integration sites (2014)
  • Author(s): Firouzi S, Yamochi T, Lopez O, Suzuki Y, Nakai K, Sugano S, Watanabe T, ”Monitoring clonal composition of HTLV-1-infected cells based on provirus integration sites
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜、横浜、
  • Year and Date: 2014-11-27
• [Presentation] HTLV-1 PVLと HLA Class I結合peptideの乖離時間との関連」、第62回日本ウイルス学会学術総会 (2014)
  • Author(s): 相良康子、井上由紀子、守田麻衣子、後藤信代、岩永正子、矢持忠徳、渡邉俊樹、浜口功、相良康弘、清川博之、
  • Organizer: 第62回日本ウイルス学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-11-11
• [Presentation] CD30 expressing cells in HTLV-1 carriers reveal abnormal nuclear morphology resembling flower cells (2014)
  • Author(s): Nakashima M, Yamochi T, Higashihara M, Watanabe T, Horie R,
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-11-01
• [Presentation] Tumor-specific gene expression leads to p38 and Hedgehog signaling activation in adult T cell leukemia (2014)
  • Author(s): Yamagishi M, Takahashi R, Sakai N, Fujikawa D, Nakagawa S, Yamochi T, Yamochi T, Nakano K, Uchimaru K, Utsunomiya A, Watanabe T
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-11-01
• [Presentation] 12カラー・フローサイトメトリーによるATLに対する樹状細胞療法後のATL細胞と免疫細胞の同時解析 (2014)
  • Author(s): 渡辺恵理、佐藤奈津子、末廣陽子、崔日承、末廣陽子、鵜池直邦、渡辺信和、
  • Organizer: 第76回日本血液学会、
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-11-01
• [Presentation] Establishment of a stroma-dependent ATL cell-line and analysis of its proliferation in vivo (2014)
  • Author(s): Tomohiro Ishigaki, Seiichiro Kobayashi, Nobuhiro Ohno, Yasunori Ota, Nobukazu Watanabe, Arinobu Tojo, Hiromitsu Nakauchi, Kaoru Uchimaru,
  • Organizer: The 76th Annual Meeting of the Japanese Society of Hematology
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-11-01
• [Presentation] Putative ATL tumor initiating cellsの解析 (2014)
  • Author(s): 矢持忠徳、守田陽平、矢持淑子、Sanaz Firouzi、佐々木陽介、渡辺信和、内丸薫、宇都宮與、渡邉俊樹
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-25
• [Presentation] A new high-throughput method to investigate the clonality of HTLV-1-infected cells based on provirus integration sites (2014)
  • Author(s): Sanaz Firouzi, Tadanori Yamochi, Yosvany Lopez, Yutaka Suzuki, Kenta Nakai, Sumio Sugano, Toshiki Watanabe
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2014-09-25
• [Presentation] キメリズム解析・HLA-Flow法による臍帯血移植後の生着、ATL細胞、およびATL細胞のHLAクラスI欠失の解析 (2014)
  • Author(s): 佐藤奈津子、渡辺信和、渡辺恵理、崔日承、鵜池直邦
  • Organizer: 第1回日本HTLV-1学会
  • Place of Presentation: 東京大学医科学研究所
  • Year and Date: 2014-08-24
• [Presentation] 急性型ATLにおける細胞表面抗原のクラスタリング解析とATL幹細胞マーカーの検索 (2014)
  • Author(s): 石垣智寛、小林誠一郎、大野伸広、中野伸亮、宇都宮與、山崎聡、渡辺信和、東條有伸、中内啓光、内丸薫、
  • Organizer: 第1回日本HTLV-1学会
  • Place of Presentation: 東京大学医科学研究所
  • Year and Date: 2014-08-24
• [Presentation] CD30はHTLV-1キャリアにおける異常リンパ球に発現し、核の形態変化に関与する (2014)
  • Author(s): 中島誠、矢持忠徳、東原正明、渡邉俊樹、堀江良一
  • Organizer: 第1回日本HTLV-1学会
  • Place of Presentation: 東京大学医科学研究所
  • Year and Date: 2014-08-23
• [Presentation] A new high-throughput method to investigate the clonality of HTLV-1-infected cells based on provirus integration sites (2014)
  • Author(s): Sanaz Firouzi, Tadanori Yamochi, Yosvany López, Yutaka Suzuki, Kenta Nakai, Sumio Sugano, Toshiki Watanabe
  • Organizer: 第1回日本HTLV-1学会
  • Place of Presentation: 東京大学医科学研究所
  • Year and Date: 2014-08-23
• [Presentation] 単鎖抗体(scFv)を用いたHTLV-1感染細胞特異的miRNA輸送システムの構築 (2014)
  • Author(s): 西田亜季、長門石曉、中野和民、山岸誠、矢持忠徳、田中勇悦、津本浩平、渡邉俊樹
  • Organizer: 第1回日本HTLV-1学会学術集会
  • Place of Presentation: 東京大学医科学研究所
  • Year and Date: 2014-08-23
• [Presentation] ATLに対する臍帯血移植後のATL細胞と免疫細胞の12カラーFACS解析 (2014)
  • Author(s): 渡辺信和、佐藤奈津子、渡辺恵理、崔日承、鵜池直邦
  • Organizer: 第1回日本HTLV-1学会学術集会
  • Place of Presentation: 東京大学医科学研究所
  • Year and Date: 2014-08-23
• [Presentation] ATLに対する樹状細胞療法後のATL細胞と免疫細胞のマルチカラーFACS解析 (2014)
  • Author(s): 渡辺恵理、佐藤奈津子、渡辺信和、末廣陽子、鵜池直邦
  • Organizer: 第1回日本HTLV-1学会学術集会
  • Place of Presentation: 東京大学医科学研究所
  • Year and Date: 2014-08-23
• [Presentation] HLA-Flow法の臨床応用 (2014)
  • Author(s): 佐藤奈津子、渡辺恵理、石垣智寛、渡辺信和、キメリズム解析／HLA-Flow法の臨床応用
  • Organizer: 第24回日本サイトメトリー学会
  • Place of Presentation: 関西医科大学、枚方市
  • Year and Date: 2014-06-28
• [Presentation] 12カラーFCMによるATLに対する樹状細胞療法後のATL細胞と免疫細胞の同時解析 (2014)
  • Author(s): 渡辺恵理、佐藤奈津子、末廣陽子、鵜池直邦、渡辺信和
  • Organizer: 第24回日本サイトメトリー学会
  • Place of Presentation: 関西医科大学、枚方市
  • Year and Date: 2014-06-28
• [Presentation] 成人T細胞白血病／リンパ腫（ATLL）における、がん幹細胞ニッチの組織病理学的同定の試み (2013)
  • Author(s): 若林 翼, 矢持 忠徳, 矢持 淑子, 佐々木 陽介, Sanaz Firouzi, 滝本雅文, 渡邉 俊樹
  • Organizer: 第102回日本病理学会総会
  • Place of Presentation: ロイトン札幌
• [Presentation] Development and validation of a new high-throughput method to investigate T-cell-clonality and integration site preference among HTLV-1-infected individuals (2013)
  • Author(s): Sanaz Firouzi、矢持忠徳、Lopez Yosvany、鈴木穣、中井謙太、菅野純夫、渡邉俊樹、
  • Organizer: 第6回HTLV-1研究会・シンポジウム
  • Place of Presentation: 東京大学医科学研究所
• [Presentation] HAS-Flow法を用いたHTLV-1キャリア／くすぶり型ATL境界の検討 (2013)
  • Author(s): 小林誠一郎、渡辺恵理、石垣知寛、中野和民、矢持忠徳、山岸誠、浅沼里実、大野伸広、湯地晃一郎、渡辺信和、東條有伸、渡邉俊樹、内丸薫、
  • Organizer: 第6回HTLV-1研究会・シンポジウム
  • Place of Presentation: 東京大学医科学研究所
• [Presentation] 成人T細胞白血病(ATL)における、がん幹細胞微小環境の組織病理学的同定の試み (2013)
  • Author(s): 若林翼、矢持忠徳、矢持淑子、佐々木陽介、Sanaz Firouzi、瀧本雅文、渡邉俊樹、
  • Organizer: 第6回HTLV-1研究会・シンポジウム
  • Place of Presentation: 東京大学医科学研究所
• [Presentation] ATLにおけるTumor initiating cell探索の試み (2013)
  • Author(s): 矢持忠徳、守田陽平、矢持淑子、Sanaz Firouzi、佐々木陽介、渡辺信和、内丸薫、宇都宮與、渡邉俊樹、
  • Organizer: 第6回HTLV-1研究会・シンポジウム
  • Place of Presentation: 東京大学医科学研究所
• [Presentation] Putative ATL tumor initiating cells の解析 (2013)
  • Author(s): 矢持忠徳、守田陽平、矢持淑子、Sanaz Firoouozi、佐々木陽介、若林翼、渡辺信和、内丸薫、宇都宮與、渡邉俊樹、
  • Organizer: 第72回日本癌学会学術総会、
  • Place of Presentation: パシフィコ横浜
• [Presentation] The CD7 vs CADM1 plot in FACS is useful for selecion of advanced HTLV-1 carriers (2013)
  • Author(s): Kobayashi S, Watanabe E, Ishigaki T, Ohno N, Yuji K, Nakano K, Yamochi T, Watanabe T, Watanabe N, Tojo A, Uchimaru K,
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: ロイトン札幌
• [Presentation] 免疫不全マウスに連続継代移植されたヒト腫瘍細胞の継代５代目における染色体解析 (2013)
  • Author(s): 佐藤均、Sanaz Firouzi、渡邉俊樹、矢持忠徳、
  • Organizer: 染色体学会第64回年会
  • Place of Presentation: 富山大学五福キャンパス
• [Presentation] Development of a new high-throughput method to investigate T-cell-clonality and integration site preference among HTLV-1 infected individuals (2012)
  • Author(s): Firouzi Sanaz、青木桜、鈴木穣、矢持忠徳、中野和民、中井謙太、菅野純夫、渡邉俊樹、
  • Organizer: 平成24年度東京大学医科学研究所研究成果発表会
  • Place of Presentation: 東京大学医科学研究所
• [Presentation] 成人T細胞性白血病におけるTumor Initiating Cellの探索の試み (2012)
  • Author(s): 矢持忠徳、守田洋平、矢持淑子、佐々木陽介、渡辺信和、Sanaz Firouzi、内丸薫、宇都宮與、渡邉俊樹，
  • Organizer: 東京大学医科学研究所
  • Place of Presentation: 東京大学医科学研究所
• [Presentation] 「成人性T細胞性白血病におけるがん幹細胞の同定への試み」 (2012)
  • Author(s): 矢持忠徳、守田陽平、矢持淑子、サナズ フィルジ、佐々木陽介、渡辺信和、内丸 薫、宇都宮與、渡邉俊樹、
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌
• [Presentation] HIV-1由来antisense RNAによるウイルス複製抑制メカニズムの解析 (2012)
  • Author(s): 小林美栄、山岸誠、松田有加、中野和民、矢持忠徳、石田尚臣、渡邉俊樹、
  • Organizer: 第60回日本ウイルス学会学術集会
  • Place of Presentation: 大阪国際会議場
• [Presentation] HIV-1由来新規antisense RNA,ASP-Lはウイルスを制御する機能性RNAである」 (2012)
  • Author(s): 小林(石原)美栄、山岸誠、松田有加、中野和民、矢持忠徳、石田尚臣、渡邉俊樹、
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場
• [Presentation] Development of a New High-throughout Method to Investigage T-cell-clonality and Integration Site Preference among HTLV-1-infected Individuals”, (2012)
  • Author(s): Firouzi S, Yamochi T, Lopez Y, Aoki S, Suzuki Y, Nakano K, Nakai K, Sugano S, Watanabe T,
  • Organizer: 第35回日本分子生物学会年会、
  • Place of Presentation: 福岡国際会議場
• [Presentation] Development of a new high-throughput method to investigate T-cell-clonality and integration site preference among HTLV-1 infected individuals (2012)
  • Author(s): Firouzi Sanaz、青木桜、鈴木穣、矢持忠徳、中野和民、中井謙太、菅野純夫、渡邉俊樹、
  • Organizer: NGS現場の会・第二回研究会
  • Place of Presentation: ホテル阪急エキスポパーク