Molecular mechanisms of leukemogenesis and stem cell regulation

• Project/Area Number: 17H04227
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Mie 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: ¥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)
• Keywords: MLL / 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。

Research Products

• [Journal Article] A Staphylococcus pro-apoptotic peptide induces acute exacerbation of pulmonary fibrosis. (2020)
  • Author(s): D'Alessandro-Gabazza CN, Kobayashi T, ・・・Nosaka T（27番目/35人）, ・・・, Cann I, Gabazza EC.
  • Journal Title: Nat Commun Volume: 11 Pages: 1539
  • DOI: 10.1038/s41467-020-15344-3
  • 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 Pages: 686-691
  • DOI: 10.1007/s12185-020-02832-x
  • 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: - Pages: -
• [Journal Article] A versatile platform technology for recombinant vaccines using non-propagative human parainfluenza virus type 2 vector. (2019)
  • 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: Sci Rep Volume: 9 Pages: 12901
  • DOI: 10.1038/s41598-019-49579-y
  • Peer Reviewed / Open Access
• [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.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Nucleocytoplasmic shuttling of the human parainfluenza virus type 2 phosphoprotein. (2019)
  • Author(s): Ohtsuka J, Matsumoto Y, Ohta K, Fukumura M, Tsurudome M, Nosaka T, Nishio M.
  • Journal Title: Virology Volume: 528 Pages: 54-63
  • DOI: 10.1016/j.virol.2018.12.005.
  • 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 interaction. (2018)
  • Author(s): Tsurudome M, Ohtsuka J, Ito M, Nishio M, Nosaka T.
  • Journal Title: Front Microbiol Volume: 9 Pages: 391
  • DOI: 10.3389/fmicb.2018.00391.
  • 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 Pages: 471-481
  • DOI: 10.1093/intimm/dxy046.
  • 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: 37 Pages: e00585-16
  • DOI: 10.1128/MCB.00585-16.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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 Pages: 1166-1173
  • DOI: 10.1002/cncr.30404.
  • 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 Pages: 682-686.e7
  • DOI: 10.1016/j.jaci.2016.05.044.
  • 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.
  • 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
• [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).
  • 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
• [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
• [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
• [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
• [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
  • 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/