Development of an epoch-making method for identification of Down syndrome patients with TAM who will subsequently develop acute megakaryoblastic leukemia

• Project/Area Number: 15K15384
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Hirosaki University
• Principal Investigator: Ito Etsuro 弘前大学, 医学研究科, 教授 (20168339)
• Co-Investigator(Kenkyū-buntansha): 土岐 力 弘前大学, 医学研究科, 講師 (50195731) ; 照井 君典 弘前大学, 医学研究科, 准教授 (00333740)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: TAM / Down症候群 / 急性巨核芽球性白血病 / GATA1 / 小児白血病 / ダウン症候群 / MRD / ダウン症

Outline of Final Research Achievements

The goal of this study is to develop an epoch-making method for identification of Down syndrome patients with transient abnormal myelopoiesis (TAM) who will subsequently develop acute megakaryoblastic leukemia (DS-AMKL) and establish the base for developing the prophylaxis for DS-AMKL. The results of this study are as follows. All patients with TAM and DS-AMKL have GATA1 mutations. To detect minimal residual diseases (MRD) of TAM, we developed highly sensitive methods to detect GATA1 mutations (sensitivity 0.02%) using target next-generation sequencing. We next performed whole exome sequencing of 40 sets of samples from DS-AMKL patients at diagnosis of AMKL and remission phases, and identified several novel mutational targets, which will be useful as MRD markers.

Research Products

• [Journal Article] Purification of leukemic blast cells from blood smears using laser microdissection. (2017)
  • Author(s): Matsuo H, Shiga S, Imai T, Kamikubo Y, Toki T, Terui K, Ito E, Adachi S.
  • Journal Title: Int J Hematol. Volume: 印刷中 Issue: 1 Pages: 55-59
  • DOI: 10.1007/s12185-017-2227-z
  • Peer Reviewed
• [Journal Article] Whole-exome sequencing reveals the spectrum of gene mutations and the clonal evolution patterns in paediatric acute myeloid leukaemia. (2016)
  • Author(s): Shiba N, Yoshida K, Shiraishi Y, Okuno Y, Yamato G, Hara Y, Nagata Y, Chiba K, Tanaka H, Terui K, Kato M, Park MJ, Ohki K, Shimada A, Takita J, Tomizawa D, Kudo K, Arakawa H, Adachi S, Taga T, Tawa A, Ito E, Horibe K, Sanada M, Miyano S, Ogawa S, Hayashi Y.
  • Journal Title: Br J Haematol. Volume: 175 Issue: 3 Pages: 476-489
  • DOI: 10.1111/bjh.14247
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Systematic cellular disease models reveal synergistic interactions of trisomy 21 and GATA1 mutations in hematopoietic abnormalities (2016)
  • Author(s): K. Banno, S. Omori, K. Hirata, N. Nawa, N. Nakagawa, K. Nishimura, M. Ohtaka, M. Nakanishi, T. Sakuma, T. Yamamoto, T. Toki, E. Ito, T. Yamamoto, C. Kokubu, J. Takeda, H. Taniguchi, H. Arahori, K. Wada, Y. Kitabatake and K. Ozono
  • Journal Title: Cell Reports Volume: 15 Issue: 6 Pages: 1-15
  • DOI: 10.1016/j.celrep.2016.04.031
  • NAID: 120007135439
  • Peer Reviewed / Open Access
• [Journal Article] Preserved High Probability of Overall Survival with Significant Reduction of Chemotherapy for Myeloid Leukemia in Down Syndrome: A Nationwide Prospective Study in Japan. (2016)
  • Author(s): Taga T, Watanabe T, Tomizawa D, Kudo K, Kiminori Terui K, Moritake H, Kinoshita A, Iwamoto S, Nakayama H, Takahashi H, Shimada A MD, Taki T, Toki T, Ito E, Goto H, Koh K, Saito AM, Horibe K, Nakahata T, Tawa A, Adachi S.
  • Journal Title: Pediatr Blood Cancer Volume: 63 Issue: 2 Pages: 248-54
  • DOI: 10.1002/pbc.25789
  • Peer Reviewed
• [Journal Article] Transient myeloproliferative disorder with partial trisomy 21. (2015)
  • Author(s): Takahashi T, Inoue A, Yoshimoto J, Kanamitsu K, Taki T, Imada M, Yamada M, Ninomiya S, Toki T, Terui K, Ito E, Shimada A.
  • Journal Title: Pediatr Blood Cancer Volume: 62 Issue: 11 Pages: 2021-2024
  • DOI: 10.1002/pbc.25624
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Analysis of GATA1 mutations in Down syndrome infants with transient abnormal myelopoiesis and clinical impacts of GATA1 mutation types: A report from the JPLSG TAM-10 study. (2016)
  • Author(s): Kiminori Terui, Tsutomu Toki, Asahito Hama, Hideki Muramatsu, Daisuke Hasegawa, Myoung-ja Park, Shotaro Iwamoto, Takashi Taga, Ryu Yanagisawa, Katsuyoshi Koh, Akiko M. Saito, Keizo Horibe, Yasuhide Hayashi, Souichi Adachi Shuki Mizutani, Kenichiro Watanabe and Etsuro Ito
  • Organizer: American Society of Hematology 58th Annual Meeting
  • Place of Presentation: SanDiego, CA, USA
  • Year and Date: 2016-12-03
  • Int'l Joint Research / Invited
• [Presentation] Genetic and Epigenetic Alterations in Acute Megakaryoblastic Leukemia in Down Syndrome. (2016)
  • Author(s): Etsuro Ito, Kenichi Yoshida, Tsutomu Toki, Satoshi Saida, Kenichiro Watanabe, Masahiro Nakamura, Kiminori, Terui, Tatsutoshi Nakahata, Satoru Miyano, Akira Watanabe, Seishi Ogawa
  • Organizer: Fifth JCA- AACR Special Joint Conference -The Latest Advances in Hematological Cancer Research: From Basic Science to Therapeutics.
  • Place of Presentation: Tokyo Bay Maihama Hotel, Urayasu, Chiba
  • Year and Date: 2016-07-13
  • Int'l Joint Research / Invited
• [Presentation] DNA methylation state correlates with progression of myeloid leukemia in Down syndrome. (2015)
  • Author(s): Saida S, Nakamura M, Toki T, Arai Y, Terui K, Yoshida Y, Ogawa S, Nakahata T, Heike T, Watanabe K, Watanabe A, Ito E.
  • Organizer: 第57回アメリカ血液学会
  • Place of Presentation: オーランド（米国）
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] Prospective study of 168 infants with transient abnormal myelopoiesis with Down syndrome: Japan Pediatric Leukemia/Lymphoma Study Group, TAM-10 study (2015)
  • Author(s): Muramatsu H, Watanabe T, Hasegawa D, Park M, Iwamoto S, Taga T, Ito E, Toki T, Terui K, Yanagisawa R, Koh K, Saito A, Horibe K, Hayashi Y, Adachi S, Mizutani S, Watanabe K.
  • Organizer: 第57回アメリカ血液学会
  • Place of Presentation: オーランド（米国）
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] TAMの最新情報（教育講演） (2015)
  • Author(s): 伊藤悦朗
  • Organizer: 第60回日本新生児生育医学会
  • Place of Presentation: いわて県民情報交流センター「アイーナ」，盛岡地域交流センター「マリオス」，ホテルメトロポリタン盛岡（岩手県盛岡市）
  • Year and Date: 2015-11-23
  • Int'l Joint Research / Invited
• [Book] 造血器腫瘍アトラス（改訂第 5 版） 第4章 B 急性白血病，骨髄異形成症候群各論‐5.ダウン症候群における造血器腫瘍と遺伝子突然変異‐ (2016)
  • Author(s): 伊藤悦朗
  • Publisher: 日本医事新報社