Single cell analysis of dynamic change of epigenetic abnormalities in adult T cell leukemia/lymphoma (ATL)

• Project/Area Number: 16K08667
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Okayama University
• Principal Investigator: Oka Takashi 岡山大学, 医歯薬学総合研究科, 講師 (50160651)
• Co-Investigator(Kenkyū-buntansha): 大内田 守 岡山大学, 医歯薬学総合研究科, 准教授 (80213635) ; 岡田 康志 国立研究開発法人理化学研究所, 生命機能科学研究センター, チームリーダー (50272430) ; 吉野 正 岡山大学, 医歯薬学総合研究科, 教授 (70183704)
• Project Period (FY): 2016-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: HTLV-1 / ATL / DNAメチル化 / 1細胞解析 / ライブセルイメージング / 網羅的解析 / de novo methylation / DNA methylation foci / １細胞解析 / HTLV-I / ウイルス / 腫瘍病理学 / エピジェネテイックス / 成人T細胞白血病

Outline of Final Research Achievements

Adult T-cell leukemia/lymphoma (ATL), an aggressive type of T-cell malignancy, is induced by human T-cell leukemia virus type I (HTLV-1) infection. The outcomes, following therapeutic interventions for ATL, have not been satisfactory. In the present investigation,　we established live-cell imaging method of DNA methylation using methylated DNA binding protein (MBD) fused with enhanced green fluorescent protein (EGFP); MBD-EGFP to detect dynamic changes of DNA methylation induced by endogenous and/or exogenous environmental perturbations in human leukemia cells. Comprehensive global DNA methylation and gene expression analyses revealed dynamic changes of target gene methylation and gene expression followed by HTLV1tax gene expression. In vitro live cell imaging of DNA methylation with HTLV-1tax-oncogene ON/OFF system is useful system to investigate epigenetic mechanism of ATL leukemogenesis/lymphomagenesis.

Academic Significance and Societal Importance of the Research Achievements

我々はこれまでに超微量検体を用いて造血器腫瘍のＤＮＡ異常メチル化を高感度・高精度に検出する方法を開発し、造血器腫瘍の早期診断、また低悪性度から高悪性度病型への進展可能性を評価する検査方法の開発に成功した。本研究に於いてlive cell imaging法を用いてHTLV-1tax癌遺伝子発現がＤＮＡ異常メチル化を誘発し遺伝子発現異常を引き起こすことを直接示し、そのダイナミックスを解析した。ＤＮＡ異常メチル化誘発機構と発癌との関連を明らかにすることは、エピジェネテイック制御が可逆的であることから将来悪性腫瘍の新規早期発見・早期治療法更に予防法につながる可能性があり,さらなる発展が期待される。

Research Products

• [Int'l Joint Research] University of Amsterdam/Swammerdam Institute for Life Sciences/Department of Biochemistry(オランダ)
• [Int'l Joint Research] Mansoura University/Faculty of Medicine/Department of Pathology(エジプト)
• [Int'l Joint Research] University Paris Descartes (Paris 5),/AP-HP Hopital/Necker-Enfants Malades(フランス)
• [Journal Article] Author Correction: 5-aminolevulinic acid-mediated photodynamic therapy can target aggressive adult T cell leukemia/lymphoma resistant to conventional chemotherapy (2021)
  • Author(s): Sando Yasuhisa、Matsuoka Ken-ichi、Sumii Yuichi、Kondo Takumi、Ikegawa Shuntaro、Sugiura Hiroyuki、Nakamura Makoto、Iwamoto Miki、Meguri Yusuke、Asada Noboru、Ennishi Daisuke、Nishimori Hisakazu、Fujii Keiko、Fujii Nobuharu、Utsunomiya Atae、Oka Takashi、Maeda Yoshinobu
  • Journal Title: Scientific Reports Volume: 11 Pages: 6420-6420
  • DOI: 10.1038/s41598-021-86066-9
  • Peer Reviewed / Open Access
• [Journal Article] 5-aminolevulinic acid-mediated photodynamic therapy can target aggressive adult T cell leukemia/lymphoma resistant to conventional chemotherapy (2020)
  • Author(s): Sando Yasuhisa、Matsuoka Ken-ichi、Sumii Yuichi、Kondo Takumi、Ikegawa Shuntaro、Sugiura Hiroyuki、Nakamura Makoto、Iwamoto Miki、Meguri Yusuke、Asada Noboru、Ennishi Daisuke、Nishimori Hisakazu、Fujii Keiko、Fujii Nobuharu、Utsunomiya Atae、Oka Takashi、Maeda Yoshinobu
  • Journal Title: Scientific Reports Volume: 10 Pages: 17237-17237
  • DOI: 10.1038/s41598-020-74174-x
  • NAID: 120006900788
  • Peer Reviewed / Open Access
• [Journal Article] Sensitive Photodynamic Detection of Adult T-cell Leukemia/Lymphoma and Specific Leukemic Cell Death Induced by Photodynamic Therapy: Current Status in Hematopoietic Malignancies. (2020)
  • Author(s): Oka T, Matsuoka KI, Utsunomiya A
  • Journal Title: Cancers Volume: 12(2) Pages: 335-335
  • DOI: 10.3390/cancers12020335
  • NAID: 120006840782
  • Peer Reviewed / Open Access
• [Journal Article] Metabolic abnormalities in adult T-cell leukemia/lymphoma and induction of specific leukemic cell death using photodynamic therapy (2018)
  • Author(s): Takashi Oka, Hajime Mizuno, Masumi Sakata, Hirofumi Fujita, Tadashi Yoshino,Yoshihisa Yamano, Kozo Utsumi, Tsutomu Masujima & Atae Utsunomiya
  • Journal Title: Scientific Reports Volume: 8 Pages: 14979-14979
  • DOI: 10.1038/s41598-018-33175-7
  • Peer Reviewed / Open Access
• [Journal Article] Merkel cell polyomavirus and Langerhans cell neoplasm. (2018)
  • Author(s): Murakami I, Wada N, Nakashima J, Iguchi M, Toi M, Hashida Y, Higuchi T, Daibata M, Matsushita M, Iwasaki T, Kuwamoto S, Horie Y, Nagata K, Hayashi K, Oka T, Yoshino T, Imamura T, Morimoto A, Imashuku S, Gogusev J, Jaubert F.
  • Journal Title: Cell Communication and Signaling Volume: 16(1) Pages: 1-12
  • DOI: 10.1186/s12964-018-0261-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gene expression analysis of hypersensitivity to mosquito bite, chronic active EBV infection and NK/T-lymphoma/leukemia (2017)
  • Author(s): Kana Washio, Takashi Oka, Lamia Abdalkader, Michiko Muraoka, Akira Shimada, Megumi Oda, Hiaki Sato, Katsuyoshi Takata, Yoshitoyo Kagami, Norio Shimizu, Seiichi Kato, Hiroshi Kimura, Kazunori Nishizaki, Tadashi Yoshino & Hirokazu Tsukahara
  • Journal Title: Leuk Lymphoma Volume: 58 Pages: 1-12
  • DOI: 10.1080/10428194.2017.1304762
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Aberrant differential expression of EZH1 and EZH2 in Polycomb repressive complex 2 among B- and T/NK-cell neoplasms. (2016)
  • Author(s): Abdalkader L, Oka T, Takata K, Sato H, Murakami I, Otte AP, Yoshino T
  • Journal Title: Pathology. Volume: vol.40 Pages: 467-482
  • DOI: 10.1016/j.pathol.2016.05.002
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] EARLY DETECTION OF ADULT T-CELL LEUKEMIA/LYMPHOMA AND INDUCTION OF SPECIFIC LEUKEMIC CELL DEATH WITH 5-AMINOLEVULINIC ACID MEDIATED PHOTODYNAMIC THERAPY (2020)
  • Author(s): Takashi Oka, Hajime Mizuno, Masumi Sakata, Hirofumi Fujita, Ken-ichi Matsuoka, Tadashi Yoshino, Yoshihisa Yamano, Kozo Utsumi, Tsutomu Masujima, Yoshinobu Maeda1, and Atae Utsunomiya
  • Organizer: Nature Conference,”Transdisciplinary Cancer Interception: Leveraging
  • Int'l Joint Research / Invited
• [Presentation] EARLY DETECTION OF ADULT T-CELL LEUKEMIA/LYMPHOMA AND INDUCT ION OF SPECIFIC LEUKEMIC CELL DEATH WITH 5-AMINOLEVULINIC ACID MEDIATED PHOTODYNAMIC THERAPY (2020)
  • Author(s): Takashi Oka, Hajime Mizuno, Masumi Sakata, Hirofumi Fujita, Ken-ichi Matsuoka, Tadashi Yoshino, Yoshihisa Yamano, Kozo Utsumi, Tsutomu Masujima, Yoshinobu Maeda, and Atae Utsunomiya
  • Organizer: Nature conference, “Transdisciplinary Cancer Interception: Leveraging Biology to Improve Prevention and Detection” Organized by Huntsman Cancer Institute, Univ. of Utah and Nature Reviews Cancer
  • Int'l Joint Research / Invited
• [Presentation] 成人T細胞白血病／リンパ腫（ATL）発症・進展における代謝異常と光動力学的治療法によるATL白血病細胞特異的細胞死の誘導 (2019)
  • Author(s): 岡 剛史、水野 初、 阪田真澄、藤田洋史、吉野 正、山野嘉久、内海耕造、升島 努、宇都宮與
  • Organizer: 第59回日本リンパ網内系学会総会
• [Presentation] Dynamic Changes and aberrant differential expression of EZH1 and EZH2 in Polycomb repressive complex 2 among B- and T/NK-cell neoplasms (2019)
  • Author(s): Takashi Oka
  • Organizer: 17th Annual Congress of International Drug Discovery Science & Technology (IDDST-2019)
  • Int'l Joint Research / Invited
• [Presentation] ATL発症・進展における漸進的代謝異常と光動力学的治療法によるATL白血病細胞特異的細胞死の誘導 (2019)
  • Author(s): 岡 剛史、水野 初、 阪田真澄、藤田洋史、吉野 正、山野嘉久、内海耕造、升島 努、宇都宮與
  • Organizer: 第6回日本HTLV-1学会学術集会
• [Presentation] Sensitive detection of metabolic abnormalities in adult T-cell leukemia/lymphoma and induction of specific leukemic cell death using photodynamic therapy (2019)
  • Author(s): Takashi Oka
  • Organizer: 3rd World Congress on Cancer “New strategies to prevent, diagnose and treat Cancer based on Precision Medicine”
  • Int'l Joint Research / Invited
• [Presentation] Dynamic changes of metabolic abnormalities in adult T-cell leukemia/lymphoma and induction of specific leukemic cell death using photodynamic therapy (2019)
  • Author(s): Takashi Oka, Hajime Mizuno, Masumi Sakata, Hirofumi Fujita, Ken-ichi Matsuoka, Tadashi Yoshino, Yoshihisa Yamano, Kozo Utsumi, Tsutomu Masujima, Yoshinobu Maeda, and Atae Utsunomiya
  • Organizer: 日本分子生物学会
• [Presentation] Sensitive detection of dynamic changes of metabolic abnormalities during onset and progression of adult T-cell leukemia/lymphoma (ATL) and induction of specific leukemic cell death by photodynamic action (2017)
  • Author(s): Takashi Oka, Masumi Sakata, Hajime Mizuno, Hirofumi Fujita, Tsutomu Masujima, Tadashi Yoshino, Yoshihisa Yamano and Atae Utsunomiya
  • Organizer: The18th International Conference on Human Retrovirology: HTLV and Related Viruses HTLV
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2017-03-07
  • Int'l Joint Research
• [Presentation] Aberrant DNA methylation is associated with the clinical course in the same patients with ATL (2017)
  • Author(s): Hiaki Sato, Takashi Oka, Yoko Shinnou-Nakatani, Kana Washio, Ichiro Murakami, Mamoru Ouchida, Atae Utsunomiya, Tadashi Yoshino
  • Organizer: The18th International Conference on Human Retrovirology: HTLV and Related Viruses HTLV
  • Place of Presentation: Tokyo, Japan
  • Year and Date: 2017-03-07
  • Int'l Joint Research
• [Presentation] Sensitive detection of dynamic changes of metabolic abnormalities during onset and progression of adult T-cell leukemia/lymphoma (ATL) and induction of specific leukemic cell death by photodynamic action (2017)
  • Author(s): Takashi Oka, Masumi Sakata, Hajime Mizuno, Hirofumi Fujita, Tsutomu Masujima, Tadashi Yoshino, Yoshihisa Yamano, Atae Utsunomiya
  • Organizer: 18th International Conference on Human Retrovirology：HTLV and Related Viruses
  • Int'l Joint Research
• [Presentation] Aberrant DNA methylation is associated with the clinical course in the same patients with ATL. (2017)
  • Author(s): Hiaki Sato, Takashi Oka, Yoko Shinnou-Nakatani, Kana Washio, Ichiro Murakami, Mamoru Ouchida, Atae Utsunomiya, Tadashi Yoshino
  • Organizer: 18th International Conference on Human Retrovirology：HTLV and Related Viruses
  • Int'l Joint Research
• [Presentation] 成人T細胞白血病/リンパ腫（ATL）におけるDNA異常メチル化と病態の変動との関連 (2017)
  • Author(s): 佐藤妃映、岡 剛史、神農陽子、鷲尾佳奈、村上一郎、大内田守、宇都宮與、吉野 正
  • Organizer: 日本病理学会総会
• [Presentation] 成人T細胞白血病/リンパ腫（ATL）を発症したHTLV-1キャリアにおける異常DNAメチル化の解析 (2017)
  • Author(s): 佐藤妃映、岡 剛史、神農陽子、鷲尾佳奈、村上一郎、大内田守、宇都宮與、吉野 正
  • Organizer: 日本リンパ網内系学会総会,
• [Presentation] HTLV-1キャリアにおける異常DNAメチル化と成人T細胞白血病/リンパ腫（ATL）発症との関連について (2017)
  • Author(s): 佐藤妃映、岡 剛史、神農陽子、鷲尾佳奈、村上一郎、大内田守、宇都宮與、吉野 正
  • Organizer: 日本HTLV-1学会学術集会
• [Presentation] ECOLOGY OF MERKEL CELL POLYOMAVIRUS IN HEALTHY SKIN SHOWS A CLOSE AGREEMENT WITH INTERLEUKIN-1 LOOP MODEL IN LANGERHANS CELL HISTIOCYTOSIS (2016)
  • Author(s): Ichiro Murakami, Junko Nakashima, Yumiko Hashida, Masanori Daibata, Michiko Matsushita, Takeshi Iwasaki, Satoshi Kuwamoto, Masako Kato, Keiko Nagata, Kazuhiko Hayashi, Takashi Oka, Tadashi Yoshino, Toshihiko Imamura, Akira Morimoto, Shinsaku Imashuku, Jean Gogusev, Francis Jaubert
  • Organizer: 32nd Annual Meeting of the Histiocyte Society
  • Place of Presentation: Dublin, Irland
  • Year and Date: 2016-10-17
  • Int'l Joint Research