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Molecular mechanisms of leukemogenesis and stem cell regulation

Research Project

Project/Area Number 17H04227
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionMie University

Principal Investigator

Nosaka Tetsuya  三重大学, 医学系研究科, 教授 (30218309)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2019: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2017: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
KeywordsMLL / Eya2 / E2A-HLF / 白血病 / 染色体転座 / 造血幹細胞 / Tet1 / PLZF / 白血病幹細胞 / 自己複製 / がん幹細胞 / MLL-ENL / 幹細胞
Outline of Final Research Achievements

We previously showed that PLZF plays a critical role in MLL-ENL-mediated leukemogenesis, and Eya2, an essential gene for eye development in Drosophila, was found to be important as a downstream molecule of PLZF in the leukemogenesis. Here we report that Eya2 has a critical role in leukemogenesis by E2A-HLF, a responsible gene for one of the most aggressive pediatric lymphoid leukemias, suggesting Eya2 as a possible target for a molecular therapy against therapy-resistant leukemias. Meanwhile, Tet1, one of the upregulated genes downstream of MLL-ENL, has been found to give no effects on the phenotype of MLL-ENL-mediated leukemia, by analyses using Tet1 conditional knockout mice we have developed.

Academic Significance and Societal Importance of the Research Achievements

小児の白血病は比較的予後が良いものが多いが、中には予後不良のものがある。小児急性リンパ性白血病の原因遺伝子の一つにE2A-HLFが知られているが、同遺伝子によって発症した白血病は予後が悪く、その分子機構も不明な点が多い。我々はE2A-HLFによって生じる白血病発症の分子機構としてEya2という転写活性化因子の関与を明らかにした。このことによって、難治性白血病に対する将来の分子標的療法の可能性を開いたと言える。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (20 results)

All 2020 2019 2018 2017 Other

All Journal Article (11 results) (of which Int'l Joint Research: 9 results,  Peer Reviewed: 10 results,  Open Access: 6 results,  Acknowledgement Compliant: 1 results) Presentation (8 results) (of which Int'l Joint Research: 3 results) Remarks (1 results)

  • [Journal Article] A Staphylococcus pro-apoptotic peptide induces acute exacerbation of pulmonary fibrosis2020

    • Author(s)
      D’Alessandro-Gabazza Corina N、Kobayashi Tetsu、Yasuma Taro、Toda Masaaki、Fujimoto Hajime、Hataji Osamu、Takeshita Atsuro、Nishihama Kota、Okano Tomohito、Okano Yuko、Nishii Yoichi、Tomaru Atsushi、Fujiwara Kentaro、D’Alessandro Valeria Fridman、Yano Yutaka、Cann Isaac、Gabazza Esteban C
    • Journal Title

      Nature Communications

      Volume: 11 Issue: 1 Pages: 1539-1539

    • DOI

      10.1038/s41467-020-15344-3

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Genetic polymorphisms and vincristine-induced peripheral neuropathy in patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone therapy.2020

    • Author(s)
      Sawaki A, Miyazaki K, Yamaguchi M, Takeuchi T, Kobayashi K, Imai H, Tawara I, Ono R, Nosaka T, Katayama N.
    • Journal Title

      Int J Hematol

      Volume: 111 Issue: 5 Pages: 686-691

    • DOI

      10.1007/s12185-020-02832-x

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 血液腫瘍モデル動物の現状と展望. In: 金倉譲 編集. 造血器腫瘍学-基礎と臨床の最新研究動向-.2020

    • Author(s)
      小埜良一、野阪哲哉.
    • Journal Title

      日本臨床

      Volume: -

    • Related Report
      2019 Annual Research Report
  • [Journal Article] A versatile platform technology for recombinant vaccines using non-propagative human parainfluenza virus type 2 vector2019

    • Author(s)
      Ohtsuka J, Fukumura M, Furuyama W, Wang S, Hara K, Maeda M, Tsurudome M, Miyamoto H, Kaito A, Tsuda N, Kataoka Y, Mizoguchi A, Takada A, Nosaka T.
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 1-9

    • DOI

      10.1038/s41598-019-49579-y

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Eya2 is critical for E2A-HLF-mediated immortalization of mouse hematopoietic stem/progenitor cells.2019

    • Author(s)
      Maharjan BD, Ono R, Nosaka T.
    • Journal Title

      Int J Oncol

      Volume: 54 Pages: 981-990

    • DOI

      10.3892/ijo.2019.4673

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Nucleocytoplasmic shuttling of the human parainfluenza virus type 2 phosphoprotein2019

    • Author(s)
      Ohtsuka Junpei、Matsumoto Yusuke、Ohta Keisuke、Fukumura Masayuki、Tsurudome Masato、Nosaka Tetsuya、Nishio Machiko
    • Journal Title

      Virology

      Volume: 528 Pages: 54-63

    • DOI

      10.1016/j.virol.2018.12.005

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] The Hemagglutinin-Neuraminidase (HN) Head Domain and the Fusion (F) Protein Stalk Domain of the Parainfluenza Viruses Affect the Specificity of the HN-F Interaction2018

    • Author(s)
      Tsurudome Masato、Ohtsuka Junpei、Ito Morihiro、Nishio Machiko、Nosaka Tetsuya
    • Journal Title

      Front Microbiol.

      Volume: 9 Pages: 391-391

    • DOI

      10.3389/fmicb.2018.00391

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Immunological association of inducible bronchus-associated lymphoid tissue organogenesis in Ag85B-rHPIV2 vaccine-induced anti-tuberculosis mucosal immune responses in mice.2018

    • Author(s)
      Nagatake T, Suzuki H, Hirata S, Matsumoto N, Wada Y, Morimoto S, Nasu A, Shimojou M, Kawano M, Ogami K, Tsujimura Y, Kuroda E, Iijima N, Hosomi K, Ishii KJ, Nosaka T, Yasutomi Y, Kunisawa J.
    • Journal Title

      Int Immunol

      Volume: 30 Issue: 10 Pages: 471-481

    • DOI

      10.1093/intimm/dxy046

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Eya2, a target activated by Plzf, is critical for PLZF-RARA-induced leukemogenesis.2017

    • Author(s)
      Ono R, Masuya M, Ishii S, Katayama N, Nosaka T.
    • Journal Title

      Mol Cell Biol

      Volume: 印刷中 Issue: 13

    • DOI

      10.1128/mcb.00585-16

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] MYD88, CD79B, and CARD11 gene mutations in CD5-positive diffuse large B-cell lymphoma.2017

    • Author(s)
      Takeuchi, T, Yamaguchi M, Kobayashi K, Miyazaki K, Tawara I, Imai H, Ono R, Nosaka T, Tanaka K, Katayama N.
    • Journal Title

      Cancer

      Volume: 123 Issue: 7 Pages: 1166-1173

    • DOI

      10.1002/cncr.30404

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Restrictive interleukin-10 induction by an innocuous Parainfluenza virus vector ameliorates nasal allergy.2017

    • Author(s)
      Yamanaka K, Nakanishi T, Isono K, Hasegawa C, Inada Y, Mizutani K, Matsushima Y, Okada K, Mabuchi T, Kondo M, Yamagiwa A, Kakeda M, Habe K, Nosaka T, Gabazza EC, Yamazaki H, Mizutani H, Kawano M.
    • Journal Title

      J Allergy Clin Immunol

      Volume: 139 Issue: 2 Pages: 682-686

    • DOI

      10.1016/j.jaci.2016.05.044

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] Gene mutations and sites of involvement in duodenal-type follicular lymphoma.2019

    • Author(s)
      Miyazaki K, Takeuchi T, Yamaguchi M, Asano N, Sawaki A, Imai H, Ono R, Nosaka T, Kobayashi K, Tanaka K, Katayama N.
    • Organizer
      15 ICML-International Conference on Malignant Lymphoma.
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 十二指腸濾胞性リンパ腫における遺伝子変異と浸潤部位.2019

    • Author(s)
      宮崎 香奈, 竹内 俊文, 山口 素子, 浅野 直子, 澤木 昭彦, 今井 裕, 小埜 良一, 野阪 哲哉, 小林 一彦, 田中 匡介, 片山 直之
    • Organizer
      第81回日本血液学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Gene polymorphisms and vincristine-induced neuropathy in patients who received R-CHOP chemotherapy.2019

    • Author(s)
      Sawaki A, Miyazaki K, Takeuchi T, Kobayashi K, Imai H, Tawara I, Ono R, Nosaka T, Yamaguchi M, Katayama N.
    • Organizer
      61th Annual Meeting & Exposition of the ASH (American Society of Hematology).
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Immunological association of inducible bronchus-associated lymphoid tissue organogenesis in Ag85B-rHPIV2 vaccine-induced anti-tuberculosis mucosal immune responses in mice.2018

    • Author(s)
      Nagatake T, Suzuki H, Kawano M, Ogami K, Tsujimura Y, Kuroda E, Iijima N, Hosomo K, Ishii KJ, Yasutomi Y, Kunisawa J, (non-JSI member contributors: Hirata S, Nosaka T).
    • Organizer
      第47回 日本免疫学会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Organogenesis of inducible bronchus-associated lymphoid tissue plays an essential role in Ag85B-hPIV2-based anti-tuberculosis respiratory vaccine in mice.2018

    • Author(s)
      Nagatake T, Suzuki H, Nasu A, Hirata S, Wada Y, Matsumoto N, Shimojou M, Morimoto S, Hosomi K, Ogami K, Tsujimura Y, Kawano M, Nosaka T, Yasutomi Y, Kunisawa J.
    • Organizer
      第11回次世代アジュバント研究会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Eya2 is critical for an aberrant self-renewal in PLZF-RARA-induced leukemogenesis.2017

    • Author(s)
      Ono R, Masuya M, Ishii S, Katayama N, Nosaka T.
    • Organizer
      第79回日本血液学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Specified amino acids at the dimer interface of the parainfluenza virus HN head domain are required for the virus-specific HN-F interaction.2017

    • Author(s)
      Tsurudome M, Ito M, Nishio M, Nosaka T.
    • Organizer
      第65回日本ウイルス学会学術集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] A structure-based vaccine by a non-transmissible human parainfluenza virus vector.2017

    • Author(s)
      Fukumura M, Ohtsuka J, Tsurudome M, Mizoguchi A, Takada A, Tsuji M, Nosaka T.
    • Organizer
      2017 International Society for Vaccines (ISV) Annual Congress
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Remarks] 三重大学大学院医学系研究科 感染症制御医学・分子遺伝学分野

    • URL

      http://www.medic.mie-u.ac.jp/microbiol/

    • Related Report
      2018 Annual Research Report

URL: 

Published: 2017-04-28   Modified: 2021-02-19  

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