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Multistep molecular mechanisms for acute megakaryoblastic leukemia in Down syndrome

Research Project

Project/Area Number 18H04039
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 52:General internal medicine and related fields
Research InstitutionHirosaki University

Principal Investigator

Ito Etsuro  弘前大学, 医学研究科, 特任教授 (20168339)

Co-Investigator(Kenkyū-buntansha) 照井 君典  弘前大学, 医学研究科, 教授 (00333740)
工藤 耕  弘前大学, 医学部附属病院, 助教 (20455728)
土岐 力  弘前大学, 医学研究科, 講師 (50195731)
金崎 里香  弘前大学, 医学研究科, 助教 (60722882)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥44,070,000 (Direct Cost: ¥33,900,000、Indirect Cost: ¥10,170,000)
Fiscal Year 2020: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000)
Fiscal Year 2019: ¥13,780,000 (Direct Cost: ¥10,600,000、Indirect Cost: ¥3,180,000)
Fiscal Year 2018: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000)
Keywordsダウン症候群 / TAM / 急性巨核芽球性白血病 / MYC/E2F経路 / GATA1 / 付加的遺伝子異常 / 急性巨核芽性白血病
Outline of Final Research Achievements

About 10% of neonates with Down syndrome (DS: trisomy 21) develop TAM, which is characterized by rapid proliferation of abnormal blast cells. It frequently progresses to acute megakaryoblastic leukemia (DS-AMKL) after spontaneous regression, whose mechanism has not fully been elucidated. We identified novel mutational targets including the IRX1, ZBTB7A and NFIA genes, inactivation of which is implicated in an upregulated MYC/E2F pathway. We also found frequent partial tandem duplications (PTD) affecting the RUNX1 gene, which induced leukemia in a knock-in mouse model. Highly specific to DS-AMKL, these lesions highlight the mechanism that is unique to DS-related myeloid leukemogenesis.

Academic Significance and Societal Importance of the Research Achievements

ダウン症(DS)は、多段階の白血病発症機構を解明する上で貴重な疾患である。本研究では、複数の異なる遺伝子の不活化変異により、DS-AMKL細胞でMYC/E2F経路の活性化が起こることを初めて明らかにした。共通に障害されるMYC経路などを標的にした革新的な新規治療法の開発が期待できる。さらに、21番染色体上に存在するRUNX1遺伝子のPTDをDS-AMKLで高頻度に見出した。RUNX1-PTDノックインマウスを用いて、この構造異常が実際に白血病の多段階発症に重要な役割を果たすことを明らかにした。本研究成果は、全ての白血病の発症機構の解明と治療法の開発に役立つことが期待される。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (33 results)

All 2021 2020 2019 2018

All Journal Article (25 results) (of which Int'l Joint Research: 8 results,  Peer Reviewed: 25 results,  Open Access: 13 results) Presentation (8 results) (of which Int'l Joint Research: 5 results,  Invited: 2 results)

  • [Journal Article] Post-induction MRD by FCM and GATA1-PCR are significant prognostic factors for myeloid leukemia of Down syndrome2021

    • Author(s)
      Taga Takashi, Terui Kiminori、Toki Tsutomu、Ito Etsuro、et al.
    • Journal Title

      Leukemia

      Volume: - Issue: 9 Pages: 2508-2516

    • DOI

      10.1038/s41375-021-01157-w

    • NAID

      120006988564

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Predictive factors for the development of leukemia in patients with transient abnormal myelopoiesis and Down syndrome2021

    • Author(s)
      Yamato G, Deguchi T, Terui K, Toki T, Watanabe T, Imaizumi T, Hama A, Iwamoto S, Hasegawa D, Ueda T, Yokosuka T, Tanaka S, Yanagisawa R, Koh K, Saito AM, Horibe K, Hayashi Y, Adachi S, Mizutani S, Taga T, Ito E, Watanabe K, Muramatsu H.
    • Journal Title

      Leukemia.

      Volume: 35 Issue: 5 Pages: 1480-1484

    • DOI

      10.1038/s41375-021-01171-y

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Analysis of disease model iPSCs derived from patients with a novel Fanconi anemia-like IBMFS ADH5/ALDH2 deficiency.2021

    • Author(s)
      Anfeng Mu, Asuka Hira, Akira Niwa, Mitsujiro Osawa, Kenichi Yoshida, Minako Mori, Yusuke Okamoto, Kazuko Inoue, Keita Kondo, Masato T. Kanemaki, Tomonari Matsuda, Etsuro Ito, Seiji Kojima, Tatsutoshi Nakahata, Seishi Ogawa, Keigo Tanaka, Keitaro Matsuo, Megumu K. Saito, Minoru Takata.
    • Journal Title

      Blood

      Volume: 137 Issue: 15 Pages: 2021-2032

    • DOI

      10.1182/blood.2020009111

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Down syndrome-related transient abnormal myelopoiesis is attributed to a specific erythro-megakaryocytic subpopulation with GATA1 mutation.2021

    • Author(s)
      Nishinaka-Arai Y, Niwa A, Matsuo S, Kazuki Y, Yakura Y, Hiroma T, Toki T, Sakuma T, Yamamoto T, Ito E, Oshimura M, Nakahata T, Saito MK.
    • Journal Title

      Haematologica

      Volume: 106(2) Issue: 2 Pages: 635-640

    • DOI

      10.3324/haematol.2019.242693

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Two aldehyde clearance systems are essential to prevent lethal formaldehyde accumulation in mice and humans.2020

    • Author(s)
      Dingler FA†, Wang M†, Mu A† (Co-first), ....Takata M, Patel KJ.
    • Journal Title

      Mol Cell

      Volume: 80 Issue: 6 Pages: 996-1012

    • DOI

      10.1016/j.molcel.2020.10.012

    • NAID

      120006951779

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Outcome of colorectal cancer in Diamond-Blackfan syndrome with a ribosomal protein S19 mutation2020

    • Author(s)
      Kimura Kazuya、Shimazu Kazuhiro、Toki Tsutomu、Misawa Momoko、Fukuda Koji、Yoshida Taichi、Taguchi Daiki、Fukuda Sho、Iijima Katunori、Takahashi Naoto、Ito Etsuro、Nanjyo Hiroshi、Shibata Hiroyuki
    • Journal Title

      Clinical Journal of Gastroenterology

      Volume: 13 Issue: 6 Pages: 1173-1177

    • DOI

      10.1007/s12328-020-01176-7

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Reduced-intensity conditioning is effective for hematopoietic stem cell transplantation in young pediatric patients with Diamond?Blackfan anemia2020

    • Author(s)
      Koyamaishi Shun、Ogawa Seishi et al.
    • Journal Title

      Bone Marrow Transplantation

      Volume: 56 Issue: 5 Pages: 1013-1020

    • DOI

      10.1038/s41409-020-01056-1

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Clinical, cytogenetic, and molecular analyses of 17 neonates with transient abnormal myelopoiesis and nonconstitutional trisomy 212020

    • Author(s)
      Yuzawa Kentaro、Terui Kiminori、Toki Tsutomu、Kanezaki Rika、Kobayashi Akie、Sato Tomohiko、Kamio Takuya、Kudo Ko、Sasaki Shinya、Endo Mikiya、Ozono Shuichi、Nomura Keiko、Ito Etsuro
    • Journal Title

      Pediatric Blood & Cancer

      Volume: 67 Issue: 4

    • DOI

      10.1002/pbc.28188

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients.2020

    • Author(s)
      Mori M, Hira A, Yoshida K, Muramatsu H, Okuno Y, Shiraishi Y, Anmae M, Yasuda J, Tadaka S, Kinoshita K, Osumi T, Noguchi Y, Adachi S, Kobayashi R, Kawabata H, Imai K, Morio T, Tamura K, Takaori-Kondo A, Yamamoto M, Miyano S, Kojima S, Ito E, Ogawa S, Matsuo K, Yabe H, Yabe M, Takata M.
    • Journal Title

      Haematologica

      Volume: 105 Issue: 4 Pages: 1166-116

    • DOI

      10.3324/haematol.2019.245720

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A pediatric case of secondary T-cell acute lymphoblastic leukemia with KMT2A-MAML2 developing after hepatoblastoma treatment2020

    • Author(s)
      Takahashi Y, Terui K, Chinen Y, Tandai S, Kudo K, Sasaki S, Tono C, Taki T, Ito E
    • Journal Title

      Pediatr Blood Cancer

      Volume: 67 Issue: 1

    • DOI

      10.1002/pbc.28033

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Highly sensitive detection of GATA1 mutations in patients with myeloid leukemia associated with Down syndrome by combining Sanger and targeted next generation sequencing.2019

    • Author(s)
      Terui K, Toki T, Taga T, Iwamoto S, Miyamura T, Hasegawa D, Moritake H, Hama A, Nakashima K, Kanezaki R, Kudo K, Saito AM, Horibe K, Adachi S, Tomizawa D, Ito E.
    • Journal Title

      Genes Chromosomes Cancer.

      Volume: - Issue: 3 Pages: 160-167

    • DOI

      10.1002/gcc.22816

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A Rapid Cytologic Double Staining of Epstein-Barr Virus-encoded Small RNA and Cell Surface Markers for Diagnosis of Epstein-Barr Virus-associated Hemophagocytic Lymphohistiocytosis2019

    • Author(s)
      Takahashi N, Kudo K, Tanaka M, Kumagai N, Sato T, Kamio T, Sasaki S, Terui K, Kurose A, Yanagisawa R, Nakazawa Y, Ito E.
    • Journal Title

      J Pediatr Hematol Oncol.

      Volume: - Issue: 8 Pages: 1-1

    • DOI

      10.1097/mph.0000000000001647

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Study of pathophysiology and molecular characterization of congenital anemia in India using targeted next-generation sequencing approach2019

    • Author(s)
      Kedar PS, Harigae H, Ito E, Muramatsu H, Kojima S, Okuno Y, Fujiwara T, Dongerdiye R, Warang PP, Madkaikar MR
    • Journal Title

      Int J Hematol

      Volume: 60 Issue: 5 Pages: 408-416

    • DOI

      10.1007/s12185-019-02716-9

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Integrated genetic and epigenetic analysis revealed heterogeneity of acute lymphoblastic leukemia in Down syndrome2019

    • Author(s)
      Kubota Yasuo、Ogawa Seishi., et al.
    • Journal Title

      Cancer Science

      Volume: 110 Issue: 10 Pages: 3358-3367

    • DOI

      10.1111/cas.14160

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Resistance of t(17;19)-acute lymphoblastic leukemia cell lines to multiagents in induction therapy.2019

    • Author(s)
      Watanabe A, Inukai T, Kagami K, Abe M, Takagi M, Fukushima T, Fukushima H, Nanmoku T, Terui K, Ito T, Toki T, Ito E, Fujimura J, Goto H, Endo M, Look T, Kamps M, Minegishi M, Takita J, Inaba T, Takahashi H, Ohara A, Harama D, Shinohara T, Somazu S, Oshiro H, Akahane K, Goi K, Sugita K.
    • Journal Title

      Cancer Med.

      Volume: 7 Issue: 11 Pages: 5274-5288

    • DOI

      10.1002/cam4.2356

    • NAID

      120007159553

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mechanisms of Progression of Myeloid Preleukemia to Transformed Myeloid Leukemia in Children with Down Syndrome2019

    • Author(s)
      Labuhn Maurice、Ogawa Seishi., et al.
    • Journal Title

      Cancer Cell

      Volume: 36 Issue: 2 Pages: 123-138

    • DOI

      10.1016/j.ccell.2019.06.007

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] KLF1 mutation E325K induces cell cycle arrest in erythroid cells differentiated from congenital dyserythropoietic anemia patient-specific induced pluripotent stem cells.2019

    • Author(s)
      Kohara H, Utsugisawa T, Sakamoto C, Hirose L, Ogawa Y, Ogura H, Sugawara A, Liao J, Aoki T, Iwasaki T, Asai T, Doisaki S, Okuno Y, Muramatsu H, Abe T, Kurita R, Miyamoto S, Sakuma T, Shiba M, Yamamoto T, Ohga S, Yoshida K, Ogawa S, Ito E, Kojima S, Kanno H, Tani K.
    • Journal Title

      Exp Hematol.

      Volume: 73

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients.2019

    • Author(s)
      Mori M, Hira A, Yoshida K, Muramatsu H, Okuno Y, Shiraishi Y, Anmae M, Yasuda J, Tadaka S, Kinoshita K, Osumi T, Noguchi Y, Adachi S, Kobayashi R, Kawabata H, Imai K, Morio T, Tamura K, Takaori-Kondo A, Yamamoto M, Miyano S, Kojima S, Ito E, Ogawa S, Matsuo K, Yabe H, Yabe M, Takata M.
    • Journal Title

      Haematologica.

      Volume: - Issue: 10 Pages: 1962-1973

    • DOI

      10.3324/haematol.2018.207241

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Discontinuation of l-asparaginase and poor response to prednisolone are associated with poor outcome of ETV6-RUNX1-positive pediatric B-cell precursor acute lymphoblastic leukemia2019

    • Author(s)
      Usami Ikuya、Imamura Toshihiko、Takahashi Yoshihiro、Suenobu Souichi、et al.
    • Journal Title

      International Journal of Hematology

      Volume: 109 Issue: 4 Pages: 477-482

    • DOI

      10.1007/s12185-019-02599-w

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Zoledronic acid for relapsed Langerhans cell histiocytosis with isolated skull bone lesion.2019

    • Author(s)
      Kudo K, Tanaka T, Kobayashi A, Terui K, Ito E.
    • Journal Title

      Pediatr Int.

      Volume: 61 Issue: 3 Pages: 315-317

    • DOI

      10.1111/ped.13774

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Associations of complementation group, ALDH2 genotype, and clonal abnormalities with hematological outcome in Japanese patients with Fanconi anemia.2019

    • Author(s)
      Yabe M, Koike T, Ohtsubo K, Imai E, Morimoto T, Takakura H, Koh K, Yoshida K, Ogawa S, Ito E, Okuno Y, Muramatsu H, Kojima S, Matsuo K, Mori M, Hira A, Takata M, Yabe H.
    • Journal Title

      Ann Hematol.

      Volume: 98 Issue: 2 Pages: 271-280

    • DOI

      10.1007/s00277-018-3517-0

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Two siblings with familial neuroblastoma with distinct clinical phenotypes harboring an ALK germline mutation.2018

    • Author(s)
      Kudo K, Ueno H, Sato T, Kubo K, Kanezaki R, Kobayashi A, Kamio T, Sasaki S, Terui K, Kurose A, Yoshida K, Shiozawa Y, Toki T, Ogawa S, Ito E.
    • Journal Title

      Genes Chromosomes Cancer.

      Volume: 57 Issue: 12 Pages: 665-669

    • DOI

      10.1002/gcc.22676

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] De Novo Mutations Activating Germline TP53 in an Inherited Bone-Marrow-Failure Syndrome2018

    • Author(s)
      Toki Tsutomu、Yoshida Kenichi、Wang RuNan、Okuno Yusuke、Kataoka Keisuke、Shiraishi Yuichi、Ohga Shouichi、Kuramitsu Madoka、Hamaguchi Isao、Ohara Akira、Kanno Hitoshi、Miyano Satoru、Kojima Seiji、Ishiguro Akira、Sugita Kanji、Kenmochi Naoya、Takahashi Satoru、Eto Koji、Ogawa Seishi、Ito Etsuro
    • Journal Title

      The American Journal of Human Genetics

      Volume: 103 Issue: 3 Pages: 440-447

    • DOI

      10.1016/j.ajhg.2018.07.020

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Diplotype analysis of NUDT15 variants and 6-mercaptopurine sensitivity in pediatric lymphoid neoplasms2018

    • Author(s)
      Tsujimoto S, Osumi T, Uchiyama M, Shirai R, Moriyama T, Nishii R, Yamada Y, Kudo K, Sekiguchi M, Arakawa Y, Yoshida M, Uchiyama T, Terui K, Ito S, Koh K, Takita J, Ito E, Tomizawa D, Manabe A, Kiyokawa N, Yang JJ, Kato M.
    • Journal Title

      Leukemia

      Volume: 32 Issue: 12 Pages: 2710-2714

    • DOI

      10.1038/s41375-018-0190-1

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Effective response to azacitidine in a child with a second relapse of myeloid leukemia associated with Down syndrome after bone marrow transplantation.2018

    • Author(s)
      Uemura S, Mori T, Nagano C, Takafuji S, Nishimura N, Toki T, Terui K, Ito E, Iijima K
    • Journal Title

      Pediatr Blood Cancer.

      Volume: 0 Issue: 12

    • DOI

      10.1002/pbc.27414

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Presentation] ダウン症候群におけるTAMから急性巨核芽球性白血病への進展の仕組み2020

    • Author(s)
      伊藤悦朗
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Post-induction minimal residual disease measured by flow cytometry and deep sequencing of mutant GATA1 are both significant prognostic factors for children with myeloid leukemia and Down syndrome: a nationwide prospective study of the Japanese Pediatric Leukemia/Lymphoma Study Group.2019

    • Author(s)
      Takashi Taga, Shiro Tanaka,, Kiminori Terui, Tsutomu Toki, Etsuro Ito, et al.
    • Organizer
      American Society of Hematology 61th Annual Meetin
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] BRAFV600E-POSITIVE PRECURSORS AS MOLECULAR MARKERS OF BONE MARROW INVOLVEMENT IN PEDIATRIC LANGERHANS CELL HISTIOCYTOSIS.2019

    • Author(s)
      Ko Kudo, Rika Kanezaki, Masaru Imamura, Chihaya Imai, Masahiro Irie, Yoji Sasahara, Kumiko Ando, Harumi Kakuda, Takehiko Doi, Hiroshi Kawaguchi, Kazuko Kudo, Hirokazu Kanegane, Tsutomu Toki, and Etsuro Ito.
    • Organizer
      35th Annual Meeting of the Histiocyte Society
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Integrated genetic and epigenetic analysis elucidated expression and methylation profiles of acute lymphoblastic leukemia in Down syndrome2018

    • Author(s)
      Yasuo Kubota, Kumiko Uryu, Tatsuya Ito, Tomoko Kawai, Masafumi Seki, Tomoya Isobe, Tsutomu Toki, Kenichi Yoshida, Keisuke Kataoka, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Satoru Miyano, Akira Oka, Yasuhide Hayashi, Seishi Ogawa, Kiminori Terui, Atsushi Sato, Kenichiro Hata, Etsuro Ito, Junko Takita.
    • Organizer
      The 23th Congress of European Hematology Association
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Modelling the progression of a preleukemic stage to overt leukemia in children with Down syndrome2018

    • Author(s)
      M. Labuhn, K. Perkins, E Papaemmanuil, S Matzk, C Scheer, Kenichi Yoshida, A Schwarzer, J Taub, J Crispino, MJ Weiss, E Ito, Seishi Ogawa, ML Yaspo, PJ Campbell, D Heckl, JH Klusmann, P Vyas.
    • Organizer
      The 60th American Society of Hematology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Clinical and genetic characteristics of patients with Shwachman-Diamond syndrome in Japan2018

    • Author(s)
      Kenichiro Watanabe, Hirokazu Kanegane, Takayuki Hamabata, Kagehiro Kozuki, Katsutsugu Umeda, Asahito Hama, Yusuke Okuno, Hideki Muramatsu, Yoshiyuki Takahashi, Daisuke Hasegawa, Atsushi Manabe, Akira Ohara, Masafumi Ito, Seiji Kojima, Etsuro Ito
    • Organizer
      The 60th American Society of Hematology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ダウン症児に発症する巨核芽球性白血病におけるエピゲノム異常2018

    • Author(s)
      伊藤悦朗
    • Organizer
      第60回日本小児血液・がん学会学術集会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] ダウン症児に発症する巨核芽球性白血病におけるエピゲノム異常2018

    • Author(s)
      渡辺 亮、才田 聡、中村 正裕、土岐 力、金崎 里香、照井 君典、渡邉 健一郎、伊藤 悦朗
    • Organizer
      第80回日本血液学会学術集会
    • Related Report
      2018 Annual Research Report
    • Invited

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Published: 2018-04-23   Modified: 2022-01-27  

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