Analysis of genetic abnormalities in adult T-cell leukemia/lymphoma and elucidation of its significance

• Project/Area Number: 15K09479
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: University of Miyazaki
• Principal Investigator: Kubuki Yoko 宮崎大学, 医学部, 講師 (00284836)
• Co-Investigator(Kenkyū-buntansha): 北中 明 川崎医科大学, 医学部, 准教授 (70343308) ; 下田 和哉 宮崎大学, 医学部, 教授 (90311844)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ① 成人T細胞性白血病・リンパ腫 / TET2 / HBZ / 成人T細胞性白血病・リンパ腫 / 遺伝子変異 / 成人Ｔ細胞性白血病・リンパ腫

Outline of Final Research Achievements

In this study, analyses were performed, focusing on mutation of TET2, an epigenetic regulator, which is observed in about 10% of ATLL and is expected to be involved in the disease onset and development. Clinical analysis between TET2 mutant patients and TET2 wild-type patients revealed that extranodal lesions were more frequent in the former than the latter. In mouse model analysis, organ infiltration of lymphocytes was more enhanced in HBZ-transgenic/TET2-mutant compound mice, compared to HBZ-transgenic mice that reflect HLTV-1 chronic infection. It seems that TET2 mutation accelerates organ infiltration of ATLL cells, resulting in the disease progression.

Research Products

• [Journal Article] Effects of mogamulizumab in adult T-cell leukemia/lymphoma in clinical practice. (2017)
  • Author(s): Sekine M, Kubuki Y, Kameda T, Takeuchi M, Toyama T, Kawano N, Maeda K, Sato S, Ishizaki J, Kawano H, Kamiunten A, Akizuki K, Tahira Y, Shimoda H, Shide K, Hidaka T, Kitanaka A, Yamashita K, Matsuoka H, Shimoda K
  • Journal Title: European journal of haematology. Volume: 98 Issue: 5 Pages: 501-507
  • DOI: 10.1111/ejh.12863
  • Peer Reviewed / Open Access
• [Journal Article] Differences in Hematological and Clinical Features Between Essential Thrombocythemia Cases With JAK2- or CALR-Mutations. (2017)
  • Author(s): Kubuki Y, Shide K, Kameda T, Yamaji T, Sekine M, Kamiunten A, Akizuki K, Shimoda H, Tahira Y, Nakamura K, Abe H, Miike T, Iwakiri H, Tahara Y, Sueta M, Hashimoto K, Yamamoto S, Hasuike S, Hidaka T, Nagata K, Kitanaka A, Shimoda K
  • Journal Title: Annals of laboratory medicine. Volume: 37 Issue: 2 Pages: 159-161
  • DOI: 10.3343/alm.2017.37.2.159
  • Peer Reviewed / Open Access
• [Journal Article] <i>TET2</i> mutation in diffuse large B-cell lymphoma (2017)
  • Author(s): Kubuki Y, Yamaji T, Hidaka T, Kameda T, Shide K, Sekine M, Kamiunten A, Akizuki K, Shimoda H, Tahira Y, Nakamura K, Abe H, Miike T, Iwakiri H, Tahara Y, Sueta M, Yamamoto S, Hasuike S, Nagata K, Kitanaka A, Shimoda K
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 56 Issue: 3 Pages: 145-149
  • DOI: 10.3960/jslrt.56.145
  • NAID: 130005465221
  • ISSN: 1346-4280, 1880-9952
  • Peer Reviewed
• [Journal Article] 遺伝子解析に基づくがん治療 骨髄増殖性腫瘍(MPN/CML) (2016)
  • Author(s): 久冨木庸子、下田和哉
  • Journal Title: がん分子標的治療Vol.14 No.1 Volume: 14 Pages: 49-53
• [Journal Article] Calreticulin mutant mice develop essential thrombocythemia that is ameliorated by the JAK inhibitor ruxolitinib (2016)
  • Author(s): Kotaro Shide, Takuro Kameda, Takumi Yamaji, Masaaki Sekine, Naoki Inada, Ayako Kamiunten, Keiichi Akizuki, Kenichi Nakamura, Akira Kitanaka, Arata Honda, Akira Sawaguchi, Hiroo Abe, Tadashi Miike, Hisayoshi Iwakiri, Yoshihiro Tahara, Mitsue Sueta, Satoru Hasuike, Shojiro Yamamoto, Kenji Nagata, and Kazuya Shimoda
  • Journal Title: Leukemia Volume: 31 Issue: 5 Pages: 1136-1144
  • DOI: 10.1038/leu.2016.308
  • Peer Reviewed / Open Access
• [Journal Article] 骨髄増殖性腫瘍のWHO分類 (2016)
  • Author(s): 久冨木庸子、下田和哉
  • Journal Title: 日本臨牀増刊号 Volume: 74 Pages: 381-385
• [Journal Article] TET2 Mutation in Adult T-Cell Leukemia/Lymphoma (2015)
  • Author(s): Shimoda K, Shide K, Kameda T, Hidaka T, Kubuki Y, Kamiunten A, Sekine M, Akizuki K, Shimoda H, Yamaji T, Nakamura K, Abe H, Miike T, Iwakiri H, Tahara Y, Sueta M, Yamamoto S, Hasuike S, Nagata K, Kitanaka A
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 55 Issue: 3 Pages: 145-149
  • DOI: 10.3960/jslrt.55.145
  • NAID: 130005119614
  • ISSN: 1346-4280, 1880-9952
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gene expression profiling of loss of TET2 and/or JAK2V617F mutant hematopoietic stem cells from mouse models of myeloproliferative neoplasms. (2015)
  • Author(s): Kameda T, Shide K, Yamaji T, Kamiunten A, Sekine M, Hidaka T, Kubuki Y, Sashida G, Aoyama K, Yoshimitsu M, Abe H, Miike T, Iwakiri H, Tahara Y, Yamamoto S, Hasuike S, Nagata K, Iwama A, Kitanaka A, Shimoda K
  • Journal Title: Genom Data. Volume: 4 Pages: 102-108
  • DOI: 10.1016/j.gdata.2015.04.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Integrated molecular analysis of adult T cell leukemia/lymphoma. (2015)
  • Author(s): Kataoka K, Nagata Y, Kitanaka A, Shiraishi Y, Shimamura T, Yasunaga J, Totoki Y, Chiba K, Sato-Otsubo A, Nagae G, et al.
  • Journal Title: Nat Genet. Volume: 47(11) Issue: 11 Pages: 1304-15
  • DOI: 10.1038/ng.3415
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Loss of TET2 has dual roles in murine myeloproliferative neoplasms: disease sustainer and disease accelerator. (2015)
  • Author(s): Kameda T, Shide K, Yamaji T, Kamiunten A, Sekine M, Taniguchi Y, Hidaka T, Kubuki Y, Shimoda H, Marutsuka K, Sashida G, Aoyama K, Yoshimitsu M, Harada T, Abe H, Miike T, Iwakiri H, Tahara Y, Sueta M, Yamamoto S, Hasuike S, Nagata K, Iwama A, Kitanaka A, Shimoda K.
  • Journal Title: Blood Volume: 125 Issue: 2 Pages: 304-315
  • DOI: 10.1182/blood-2014-04-555508
  • NAID: 40020613861
  • Peer Reviewed / Open Access
• [Presentation] Effects of mogamulizumab in adult T-cell leukemia/lymphoma in clinical practice. (2017)
  • Author(s): Masaaki Sekine, Yoko Kubuki, Takuro Kameda, Masanori Takeuchi, Takanori Toyama, Noriaki Kawanom, Kouichi Maeda, Siichi Sato, Junzo Ishizaki, Hiroshi Kawano, Ayako Kamiunten, Keiichi Akizuki, Yuki Tahira, Haruko Shimoda, Kotaro Shide, Tomonori Hidaka, Akira Kitanaka, Kiyoshi Yamashita, Hitoshi Matsuoka, Kazuya Shimoda
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] 成人T細胞性白血病に対してATGを用いたハプロ移植後に中枢神経系リンパ腫を発症した1例 (2017)
  • Author(s): 秋月渓一、日高智徳、田平優貴、上運天綾子、関根雅明、亀田拓郎、幣光太郎、下田晴子、久冨木庸子、下田和哉
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] HBZ/PRKCb変異/TET2欠損の多重異常によるATLLマウスモデル作成の試み (2017)
  • Author(s): 亀田拓郎、幣光太郎、上運天綾子、大園芳範、関根雅明、田平優貴、秋月渓一、下田晴子、日髙智徳、久冨木庸子、北中明、下田和哉：
  • Organizer: 第4回日本HTLV-1学会学術集会
• [Presentation] Mogamulizumab for adult T-cell leukemia/lymphoma in clinical practice. (2016)
  • Author(s): Masaaki Sekine, Yoko Kubuki, Takuro Kameda, Masaki Takeuchi, Takanori Toyama, Noriaki Kawano, Kouichi Maeda, Siichi Sato, Junzo Ishizaki, Hiroshi Kawano, Ayako Kamiunten, Keiichi Akizuki, Yuki Tahira, Haruko Shimoda, Kotaro Shide, Tomonori Hidaka, Akira Kitanaka, Kiyoshi Yamashita, Hitoshi Matsuoka, Kazuya Shimoda
  • Organizer: 58th ASH Annual Meeting & Exposition
  • Place of Presentation: サンディエゴ（アメリカ合衆国）
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Physiological Expression of Calr Mutant Increases Cell Growth and Cytokine Independency in Human Cell Lines Expressing Mpl, and Develops Essential Thrombocythemia in Mice. (2016)
  • Author(s): Kotaro Shide, Takuro Kameda, Masaaki Sekine, Ayako Kamiunten, Keiichi Akizuki, Yuki Tahira, Tomonori Hidaka, Yoko Kubuki, Arata Honda, Akira Sawaguchi, Akira Kitanaka, Kazuya Shimoda
  • Organizer: 58th ASH Annual Meeting & Exposition
  • Place of Presentation: サンディエゴ（アメリカ合衆国）
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] CALRdel52 mutation activates the JAK-STAT pathway in coordination with MPL, and causes ET in mice. (2016)
  • Author(s): Kotaro Shide, Takuro Kameda, Masaaki Sekine, Ayako Kamiunten, Keiichi Akizuki, Yuki Tahira, Haruko Shimoda, Tomonori Hidaka, Yoko Kubuki, Arata Honda, Akira Kitanaka, Kazuya Shimoda
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2016-10-15
• [Presentation] ＴＥＴ2欠損はHBZトランスジェニックマウスの病態を増悪させる (2016)
  • Author(s): 亀田拓郎、幣光太郎、関根雅明、山路卓巳、田平優貴、秋月渓一、上運天綾子、下田晴子、日髙智徳、久冨木庸子、北中明、下田和哉
  • Organizer: 第3回日本HTLV-1学会学術集会
  • Place of Presentation: 鹿児島県市町村自治会館（鹿児島市）
  • Year and Date: 2016-08-27
• [Book] Ⅲ.白血病 E.骨髄増殖性腫瘍（MPN） 骨髄線維症の治療EBM 血液疾患の治療2017-2018 (2016)
  • Author(s): 久冨木庸子、下田和哉
  • Total Pages: 541
  • Publisher: 株式会社中外医学社