Epigenetic abnormalities during onset and progression of adult T-cell leukemia/lymphoma (ATL)

• Project/Area Number: 25460437
• 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, 助教 (50160651)
• Co-Investigator(Kenkyū-buntansha): ITO SACHIO 岡山大学, 大学院医歯薬学総合研究科, 助教 (30335624) ; OUCHIDA MAMORU 岡山大学, 大学院医歯薬学総合研究科, 准教授 (80213635) ; YOSHINO TADASHI 岡山大学, 大学院医歯薬学総合研究科, 教授 (70183704)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: ATL / エピジェネテイックス / ポリコーム / ヒストン / DNAメチル化 / 悪性リンパ腫 / マイクロアレイ / ヒストン修飾 / ポリコーム遺伝子群 / クロマチン構造変化 / HTLV-1 / ATLL / HTLV－１ / クロマチン構造変換 / ＤＮＡメチル化 / HTLV-I

Outline of Final Research Achievements

We investigated the epigenetic mechanism of onset and progression of non-Hodgikin lymphoma as well as adult T-cell leukemia/lymphoma (ATL). We found that epigenetic abnormalities including unbalanced expression of Polycomb Repressive Complex (PRC) molecules, aberrant expression of miRNA and mRNA and also aberrant DNA methylation are playing the important role in the pathogenesis of ATL. Ezh2 was strongly expressed and polycomb repressive complex PRC1.4 dominates over PRC1.2 in aggressive lymphoma variants as well as ATL. Tax protein expression induced epigenetic heterogeneity with expanding the global DNA methylation profile to generate various epigenetic clones, suggesting that Tax-mediated epigenetic clonal heterogeneity and diversity may contribute to induce leukemic transformation and more aggressive clonal progression.

Research Products

• [Journal Article] Establishment of a Langerhans cell histiocytosis lesion cell line with dermal dendritic cell characteristics. (2015)
  • Author(s): Murakami I, Gogusev J, Jaubert F, Matsushita M, Hayashi K, Miura I, Tanaka T, Oka T, Yoshino T.
  • Journal Title: Oncol Rep. Volume: ３３（１） Pages: 171-178
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Interleukin-1 loop model for pathogenesis of Langerhans cell histiocytosis (2015)
  • Author(s): Murakami I, Matsushita M, Iwasaki T, Kuwamoto S, Kato M, Nagata K, Horie Y, Hayashi K, Imamura T, Morimoto A, Imashuku S, Gogusev J, Jaubert F, Takata K, Oka T, Yoshino T.
  • Journal Title: Cell Commun Signal Volume: 13 Issue: 1 Pages: 13-13
  • DOI: 10.1186/s12964-015-0092-z
  • Peer Reviewed / Open Access
• [Journal Article] Acute-phase ITIH4 levels distinguish multi-system from single-system Langerhans cell histiocytosis via plasma peptidomics (2015)
  • Author(s): Murakami I, Oh Y, Morimoto A, Sano H, Kanzaki S, Matsushita M, Iwasaki T, Kuwamoto S, Kato M, Nagata K, Hayashi K, Imashuku S, Gogusev J, Jaubert F, Oka T, Yoshino T.
  • Journal Title: Clin Proteomics. Volume: 12 Issue: 1 Pages: 16-16
  • DOI: 10.1186/s12014-015-9089-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gene expression analysis in children with complex seizures due to influenza A(H1N1)pdm09 or rotavirus gastroenteritis， (2014)
  • Author(s): Tsuge M1, Oka T, Yamashita N, Saito Y, Fujii Y, Nagaoka Y, Yashiro M, Tsukahara H, Morishima T.
  • Journal Title: J Neurovirol. Volume: 20 Issue: 1 Pages: 73-84
  • DOI: 10.1007/s13365-013-0231-5
  • Peer Reviewed
• [Journal Article] Detection of T-cell receptor γ gene rearrangement in paraffin-embedded T or natural killer/T-cell lymphoma samples using the BIOMED-2 protocol. (2014)
  • Author(s): Miyata-Takata T, Takata K, Yamanouchi S, Sato Y, Harada M, Oka T, Tanaka T, Maeda Y, Tanimoto M, Yoshino T.
  • Journal Title: Leuk Lymphoma. Volume: 55 Issue: 9 Pages: 2161-2164
  • DOI: 10.3109/10428194.2013.871634
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Merkel cell polyomavirus DNA sequences in peripheral blood and tissues from patients with Langerhans cell histiocytosis. (2014)
  • Author(s): Murakami I, Matsushita M, Iwasaki T, Kuwamoto S, Kato M, Horie Y, Hayashi K, Imamura T, Morimoto A, Imashuku S, Gogusev J, Jaubert F, Takata K, Oka T, Yoshino T.
  • Journal Title: Hum Pathol Volume: ４５（１） Pages: 119-26
  • Peer Reviewed
• [Journal Article] Necrotic and apoptotic cells serve as nuclei for calcification on osteoblastic differentiation of human mesenchymal stem cells in vitro. (2014)
  • Author(s): Fujita H, Yamamoto M, Ogino T, Kobuchi H, Ohmoto N, Aoyama E, Oka T, Nakanishi T, Inoue K, Sasaki J
  • Journal Title: Cell Biochemistry & Function Volume: 32(1) Issue: 1 Pages: 77-86
  • DOI: 10.1002/cbf.2974
  • Peer Reviewed
• [Journal Article] High viral load of Merkel cell polyomavirus DNA sequences in Langerhans cell sarcoma tissues. (2014)
  • Author(s): Murakami I, Matsushita M, Iwasaki T, Kuwamoto S, Kato M, Horie Y, Hayashi K, Gogusev J, Jaubert F, Nakamoto S, Yamakawa M, Nakamine H, Takata K, Oka T, Yoshino T.
  • Journal Title: Infect Agent Cancer Volume: 9 Issue: 1 Pages: 15-15
  • DOI: 10.1186/1750-9378-9-15
  • Peer Reviewed / Open Access
• [Journal Article] Duodenal follicular lymphoma lacks AID but expresses BACH2 and has memory B-cell characteristics (2013)
  • Author(s): Takata K, Sato Y, Nakamura N, Tokunaka M, Miki Y, Yukie Kikuti Y, Igarashi K, Ito E, Harigae H, Kato S, Hayashi E, Oka T, Hoshii Y, Tari A, Okada H, Mohamad AA, Maeda Y, Tanimoto M, Kinoshita T, Yoshino T
  • Journal Title: Mod Pathol Volume: 26(1) Issue: 1 Pages: 22-31
  • DOI: 10.1038/modpathol.2012.127
  • NAID: 130004505772
  • Peer Reviewed
• [Journal Article] IL-17A receptor expression differs between subclasses of Langerhans cell histiocytosis, which might settle the IL-17A controversy. (2013)
  • Author(s): Murakami I, Morimoto A, Oka T, Kuwamoto S, Kato M, Horie Y, Hayashi K, Gogusev J, Jaubert F, Imashuku S, Al-Kadar LA, Takata K, Yoshino T.
  • Journal Title: Virchows Arch Volume: 462 Issue: 2 Pages: 219-228
  • DOI: 10.1007/s00428-012-1360-6
  • Peer Reviewed
• [Journal Article] In aggressive variants of non-Hodgkin lymphomas, Ezh2 is strongly expressed and polycomb repressive complex PRC1.4 dominates over PRC1.2. (2013)
  • Author(s): Abd Al Kader L, Oka T, Takata K, Sun X, Sato H, Murakami I, Toji T, Manabe A, Kimura H, Yoshino T.
  • Journal Title: Virchows Arch. Volume: 463 Issue: 5 Pages: 697-711
  • DOI: 10.1007/s00428-013-1428-y
  • NAID: 120005359111
  • Peer Reviewed
• [Journal Article] Pathogenic mechanisms of influenza A(H1N1)pdm09 infection elucidated by gene expression profiling. (2013)
  • Author(s): Yamashita N, Tsukahara H, Tsuge M, Nagaoka Y, Yashiro M, Saito Y, Fujii Y, Takashi O, Morishima T.
  • Journal Title: Pediatr Int Volume: 55 Issue: 5 Pages: 572-577
  • DOI: 10.1111/ped.12139
  • Peer Reviewed
• [Presentation] Single cell dynamics of DNA methylation induced by the Tax gene expression of HTLV-I in adult T-cell leukemia/lymphoma (2016)
  • Author(s): Takashi Oka
  • Organizer: The 9th International Symposium for Future Technology Creating Better Human Health and Society. New Horizons in Interdisciplinary Cancer Research
  • Place of Presentation: Okayama
  • Year and Date: 2016-02-05
  • Int'l Joint Research / Invited
• [Presentation] Single cell dynamics of DNA methylation perturbated by Tax gene expression of HTLV-I in adult T cell leukemia/lymphoma (ATL) (2015)
  • Author(s): Takashi Oka, Mamoru Ouchida, Yasushi Okada, Kazuo Yamagata and Tadashi Yoshino
  • Organizer: The 74rd Annual Meeting of the Japanese Cancer Association, 2015
  • Place of Presentation: Nagoya
  • Year and Date: 2015-10-08
• [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との関連 (2015)
  • 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: 第2回日本HTLV-1学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-08-21
• [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との関連 (2015)
  • 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、大島孝一、宇都宮與、吉野 正
  • Organizer: 第５５回リンパ網内系学会学術集会
  • Place of Presentation: 岡山
  • Year and Date: 2015-07-09
• [Presentation] 成人T細胞白血病／リンパ腫（ATL）発症・進展特異的な代謝異常に関するメタボローム解析 (2015)
  • Author(s): 岡 剛史、阪田真澄、水野 初、宇都宮與、藤田洋史、升島 努、吉野 正
  • Organizer: 第５５回リンパ網内系学会学術集会
  • Place of Presentation: 岡山
  • Year and Date: 2015-07-09
• [Presentation] 成人T細胞白血病/リンパ腫（ATL）における特異的DNAメチル化と病態との関連 (2015)
  • 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、大島孝一、宇都宮與、吉野 正
  • Organizer: 第104回日本病理学会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-04-30
• [Presentation] ランゲルハンス細胞組織球症患者血清の質量分析器による解析 (2015)
  • Author(s): 村上一郎、松下倫子、岩崎 健、桑本聡史、加藤雅子、堀江 靖、林 一彦、岡 剛史、吉野 正
  • Organizer: 第104回日本病理学会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-04-30
• [Presentation] 成人T細胞白血病リンパ腫に於ける一細胞DNAメチル化の変動解析 (2015)
  • Author(s): 岡 剛史，大内田守、岡田康志、上田潤，山縣一夫，吉野正
  • Organizer: 第104回日本病理学会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-04-30
• [Presentation] 成人T細胞白血病リンパ腫に於けるDNAメチル化の動的変動 (2014)
  • Author(s): 岡 剛史，大内田守、岡田康志、上田潤，山縣一夫，吉野正
  • Organizer: 第７３回日本癌学会
  • Place of Presentation: 東京
  • Year and Date: 2014-09-24 – 2014-09-27
• [Presentation] 成人T細胞白血病･リンパ腫（ATL）発症・進展に於ける代謝異常に関するメタボローム解析 (2014)
  • Author(s): 岡 剛史、阪田真澄、水野 初、宇都宮與、藤田洋史、升島 努、吉野 正
  • Organizer: 第１回日本HTLV－１学会
  • Place of Presentation: 東京
  • Year and Date: 2014-08-22 – 2014-08-24
• [Presentation] 成人T細胞白血病/リンパ腫（ATL）関連細胞株におけるDNA異常メチル化の解析 (2014)
  • 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、高橋聖之、吉野 正
  • Organizer: 第１回日本HTLV－１学会
  • Place of Presentation: 東京
  • Year and Date: 2014-08-22 – 2014-08-24
• [Presentation] 成人T細胞白血病/リンパ腫（ATL）関連細胞株における特異的DNAメチル化の解析 (2014)
  • 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、高橋聖之、吉野 正
  • Organizer: 第５３回リンパ網内系学会
  • Place of Presentation: 京都
  • Year and Date: 2014-05-17 – 2014-05-18
• [Presentation] Aberrant expression of Polycomb complex1 (PRC1) from balanced to Bmi-1/PCGF4 dominant over Mel-18/PCGF2 in malignant lymphoma (2014)
  • Author(s): Takashi Oka1, Lamia Abd Al-Kader1,4, Ichiro Murakami1,3, Tomohiro Toji1, Akihiro Manabe1, Hiaki Sato2, Katsuyoshi Takata1, and Tadashi Yoshino1
  • Organizer: 第５３回リンパ網内系学会
  • Place of Presentation: 京都
  • Year and Date: 2014-05-17 – 2014-05-18
• [Presentation] B細胞腫瘍及びT/NK腫瘍におけるポリコーム抑制性複合体２（PRC2）のEzh1 と Ezh2の特異的発現 (2014)
  • Author(s): 岡 剛史、Lamia Abd Al-Kader，高田尚良、佐藤妃映、村上一郎、都地友紘、真鍋明広、吉野 正
  • Organizer: 第103回日本病理学会
  • Place of Presentation: 広島
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 成人T細胞白血病/リンパ腫（ATL）細胞株における特異的DNAメチル化の解析 (2014)
  • 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、高橋聖之、吉野 正
  • Organizer: 第103回日本病理学会
  • Place of Presentation: 広島
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] メルケル細胞ポリオーマウイルス解析に依るランゲルハンス細胞肉腫の疾患モデル (2014)
  • Author(s): 村上一郎、松下倫子、岩崎 健、桑本聡史、加藤雅子、堀江 靖、林 一彦、前田智治、中本 周、山川光徳、中峯寛和、高田尚良、岡 剛史、吉野 正
  • Organizer: 第103回日本病理学会
  • Place of Presentation: 広島
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 成人T細胞白血病/リンパ腫（ATLL）における特異的DNAメチル化と予後との相関 (2013)
  • Author(s): 佐藤妃映、岡 剛史、Abd Al-Kader Lamia、神農陽子、鷲尾佳奈、村上一郎、大内田守、大島孝一、宇都宮與、高橋聖之、吉野 正
  • Organizer: 第102回日本病理学会
  • Place of Presentation: 札幌
• [Presentation] Expression of PcG protein members Ezh2 and Eed in aggressive variants of non-Hodgkin lymphoma (2013)
  • Author(s): Lamia Abd Al-Kader, Takashi Oka, Xu Sun1, Katsuyoshi Takata, Hiaki Sato, Ichiro Murakami, Tomohiro Toji, Akihiro Manabe, Otte AP and Tadashi Yoshino
  • Organizer: 第102回日本病理学会
  • Place of Presentation: 札幌
• [Presentation] 網羅的遺伝子発現解析およびメルケル細胞ポリオーマウイルス解析に基づくランゲルハンス細胞組織球症の疾患モデル提唱 (2013)
  • Author(s): 村上一郎、松下倫子、岩崎 健、桑本聡史、加藤雅子、堀江 靖、林 一彦、岡 剛史、吉野 正
  • Organizer: 第102回日本病理学会
  • Place of Presentation: 札幌
• [Presentation] Sensitive detection and apoptotic cell death induction of adult T-cell leukemia/lymphoma (ATL) cells with photodynamic actions (2013)
  • Author(s): Takashi Oka, Hirofumi Fujita, Lamia Abd Al-Kader, Ichiro Murakami, Atae Utsunomiya and Tadashi Yoshino
  • Organizer: The16th International Conference on Human Retrovirology: HTLV and Related Viruses HTLV 2013
  • Place of Presentation: Montreal, Quebec, Canada.
• [Presentation] 成人T細胞白血病･リンパ腫（ATL）細胞の光動力学的反応による特異的細胞死の誘導 (2013)
  • Author(s): 岡 剛史,藤田洋史、Lamia Abd Al-Kader、村上一郎、宇都宮與、吉野 正
  • Organizer: ２０１３年HTLV-I 研究会
  • Place of Presentation: 東京
• [Presentation] 成人T細胞白血病/リンパ腫（ATLL）における特異的DNAメチル化と予後との相関 (2013)
  • Author(s): 佐藤妃映、岡 剛史、Abd Al-Kader Lamia、神農陽子、鷲尾佳奈、村上一郎、大内田守、宇都宮與、高橋聖之、吉野 正
  • Organizer: ２０１３年HTLV-I 研究会
  • Place of Presentation: 東京
• [Presentation] Sensitive detection and cell death induced by ALA-mediated photodynamic actions in adult T-cell leukemia/lymphoma cells (2013)
  • Author(s): Takashi Oka, Hirofumi Fujita, Lamia Abd Al-Kader, Ichiro Murakami, Atae Utsunomiya and Tadashi Yoshino
  • Organizer: The 72th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama, Japan
• [Presentation] High expression of Ezh2, Eed and Suz-12 in the aggressive variants of non-Hodgkin lymphoma (2013)
  • Author(s): Lamia Abd Al-Kader, Takashi Oka, Katsuyoshi Takata, Hiaki Sato, Ichiro Murakami, Tomohiro Toji, Akihiro Manabe, and Tadashi Yoshino
  • Organizer: The 72th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: Yokohama, Japan
• [Presentation] Sensitive detection and specific induction of cell death in adult T-cell leukemia/lymphoma cells by photodynamic reactions
  • Author(s): Takashi Oka, Hirofumi Fujita, Lamia Abd Al-Kader, Ichiro Murakami, Atae Utsunomiya and Tadashi Yoshino
  • Organizer: The 7th International Symposium for Future Technology Creating Better Human Health and Society
  • Place of Presentation: Okayama, Japan
• [Patent(Industrial Property Rights)] EBウイルス関連NK細胞リンパ増殖性疾患からNK細胞腫瘍進展に至る疾患の検査補助のための測定方法 (2016)
  • Inventor(s): 岡 剛史、鷲尾佳奈、吉野正
  • Industrial Property Rights Holder: 国立大学法人岡山大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-012847
  • Filing Date: 2016-01-26
• [Patent(Industrial Property Rights)] 異常活性化白血球除去環流返血治療装置 (2013)
  • Inventor(s): 岡 剛史、 藤田洋史、 吉野正
  • Industrial Property Rights Holder: 国立大学法人岡山大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-130758
  • Filing Date: 2013-06-21