Molecular mechanism of stem cell leukemogenesis and regulation of hematopoietic cell growth

• Project/Area Number: 26293247
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Mie University
• Principal Investigator: Nosaka Tetsuya 三重大学, 医学(系)研究科(研究院), 教授 (30218309)
• Co-Investigator(Renkei-kenkyūsha): ONO RYOICHI 三重大学, 大学院医学系研究科, 講師 (40422414)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000); Fiscal Year 2016: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2015: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
• Keywords: PLZF / 白血病幹細胞 / 白血病モデルマウス / EYA2 / 白血病 / 自己複製 / MLL / MLL-ENL

Outline of Final Research Achievements

We found that PLZF plays a pivotal role in hematopoietic stem cell leukemogenesis by using transgenic mice conditionally expressing an MLL chimeric gene. EYA2 gene expression was found to be elevated downstream of PLZF, and EYA2 expression was sufficient to immortalize hematopoietic cells. Furthermore, EYA2 knockdown resulted in reduced growth of the hematopoietic cells immortalized by PLZF or PLZF-RARA. These results suggest that the PLZF-EYA2 axis is important in leukemogenesis.

Research Products

• [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
  • 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
  • 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
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Expressions of SH3BP5, LMO3, and SNAP25 in diffuse large B-cell lymphoma cells and their association with clinical features. (2016)
  • Author(s): Kobayashi K, Yamaguchi M, Miyazaki K, Imai H, Yokoe K, Ono R, Nosaka T, Katayama N.
  • Journal Title: Cancer Med Volume: 5 Issue: 8 Pages: 1802-1809
  • DOI: 10.1002/cam4.753
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Novel working hypothesis for pathogenesis of hematological malignancies: combination of mutations-induced cellular phenotypes determines the disease (cMIP-DD). (2016)
  • Author(s): Kitamura T, Watanabe-Okochi N, Enomoto Y, Nakahara F, Oki T, Komeno Y, Kato N, Doki N, Uchida T, Kagiyama Y, Togami K, Kawabata KC, Nishimura K, Hayashi Y, Nagase R, Saika M, Fukushima T, Asada S, Fujino T, Izawa Y, Horikawa S, Fukuyama T, Tanaka Y, Ono R, Goyama S, Nosaka T, Kitaura J, Inoue D
  • Journal Title: Journal of Biochemistry Volume: 159 Issue: 1 Pages: 17-25
  • DOI: 10.1093/jb/mvv114
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The fusion protein specificity of the parainfluenza virus hemagglutinin-neuraminidase protein is not solely defined by the primary structure of its stalk domain (2015)
  • Author(s): Tsurudome M, Ito M, Ohtsuka J, Hara K, Komada H, Nishio M, Nosaka T
  • Journal Title: Journal of Virology Volume: 89 Issue: 24 Pages: 12374-12387
  • DOI: 10.1128/jvi.01448-15
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Jak-STAT経路. In: 細胞シグナル操作法 (2015)
  • Author(s): 野阪哲哉
  • Journal Title: 生体の科学 Volume: 66 Pages: 420-421
• [Journal Article] Vero/BC-F: an efficient packaging cell line stably expressing F protein to generate single round-infectious human parainfluenza virus type 2 vector. (2014)
  • Author(s): Ohtsuka J, Fukumura M, Tsurudome M, Hara K, Nishio M, Kawano M, Nosaka T.
  • Journal Title: Gene Ther Volume: 21 Issue: 8 Pages: 775-784
  • DOI: 10.1038/gt.2014.55
  • Peer Reviewed
• [Journal Article] Recombinant Ag85B vaccine by taking advantage of characteristics of human parainfluenza type 2 virus vector showed Mycobacteria-specific immune responses by intranasal immunization. (2014)
  • Author(s): Watanabe K, Matsubara A, Kawano M, Mizuno S, Okamura T, Tsujimura Y, Inada H, Nosaka T, Matsuo K, Yasutomi Y.
  • Journal Title: Vaccine Volume: 32 Issue: 15 Pages: 1727-1735
  • DOI: 10.1016/j.vaccine.2013.11.108
  • Peer Reviewed
• [Presentation] Organogenesis of inducible bronchus-associated lymphoid tissue has essential role in the induction of antigen-specific immune responses by Ag85B-hPIV2-based anti-tuberculosis vaccine in mice. (2017)
  • 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10回次世代アジュバント研究会
  • Place of Presentation: 千里ライフサイエンスセンター(大阪府・豊中市)
  • Year and Date: 2017-01-23
• [Presentation] MYD88, CD79B, and CD79A gene mutations in CD5-positive diffuse large B-cell lymphoma. (2016)
  • Author(s): Takeuchi T, Yamaguchi M, Kobayashi K, Miyazaki K, Tawara I, Imai H, Ono R, Nosaka T, Tanaka K, Katayama N.
  • Organizer: 58th ASH(American Society of Hematology) Annual Meeting and Exposition
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] The F protein specificity of the parainfluenza virus HN protein can be modified by substituting specified amino acids in the HN head domain. (2016)
  • Author(s): Tsurudome M, Ito M, Nishio M, Nosaka T.
  • Organizer: 第64回日本ウイルス学会学術集会
  • Place of Presentation: 札幌コンベンションセンター（北海道・札幌市）
  • Year and Date: 2016-10-23
• [Presentation] Analysis of novel molecular mechanism in PLZF-mediated leukemogenesis. (2016)
  • Author(s): Ono R, Masuya M, Ishii S, Katayama N, Nosaka T.
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
  • Year and Date: 2016-10-13
• [Presentation] Inducible bronchus- associated lymphoid tissue plays an important role in the induction of antigen-specific immune response by Ag85B-hPIV2-based anti-tuberculosis vaccine in mice. (2016)
  • Author(s): Nagatake T, Wada Y, Matsumoto N, Shimojou M, Hirata S, Nasu A, Suzuki H, Hosomi K, Ogami K, Tsujimura Y, Kawano M, Nosaka T, Yasutomi Y, Kunisawa J.
  • Organizer: AAI (The American Association of Immunologists) Annual Meeting (Immunology 2016)
  • Place of Presentation: Seattle, USA
  • Year and Date: 2016-05-13
  • Int'l Joint Research
• [Presentation] Essential role of inducible bronchus-associated lymphoid tissue genesis for the induction of antigen-specific immune response by Ag85B-hPIV2-based anti-tuberculosis vaccine in mice. (2016)
  • Author(s): Nagatake T, Wada Y, Matsumoto N, Shimojou M, Hirata S, Nasu A, Suzuki H, Hosomi K, Ogami K, Tsujimura Y, Kawano M, Nosaka T, Yasutomi Y, Kunisawa J.
  • Organizer: 第9回次世代アジュバント研究会
  • Place of Presentation: 千里ライフサイエンスセンター（大阪府・豊中市）
  • Year and Date: 2016-01-19
• [Presentation] Factors that define the F protein specificity of the parainfluenza virus HN protein. (2015)
  • Author(s): Tsurudome M, Ito M, Nishio M, Komada H, Nosaka T.
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場（福岡県・福岡市）
  • Year and Date: 2015-11-22
• [Presentation] Expression of SH3BP5, LMO3 and SNAP25 in diffuse large B-cell Lymphoma cells and association with clinical features. (2015)
  • Author(s): Kobayashi K, Yamaguchi M, Miyazaki K, Imai H, Ono R, Nosaka T, Katayama N.
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県・名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] The F specificity of the Parainfluenza virus HN is not defined solely by the primary structure of the HN stalk domain. (2015)
  • Author(s): Tsurudome M, Ito M, Nishio M, Nosaka T.
  • Organizer: Negative Strand Virus Meeting 2015
  • Place of Presentation: Siena, Italy
  • Year and Date: 2015-06-14
  • Int'l Joint Research
• [Presentation] Immunological diversity of mucosa-associated lymphoid tissues for the development of mucosal vaccine. (2015)
  • Author(s): Nagatake T, Matsumoto N, Shimojou M, Suzuki H, Fukuyama S, Sato S, Ogami K, Tsujimura Y, Kawano M, Nosaka T, Kiyono H, Yasutomi Y, Kunisawa J.
  • Organizer: 第8回次世代アジュバント研究会
  • Place of Presentation: 千里ライフサイエンスセンター
  • Year and Date: 2015-01-20
• [Presentation] Expression of LMO3 and SNAP25 in diffuse large B-cell lymphoma cells and its relation to clinical features. (2014)
  • Author(s): Kobayashi K, Yamaguch M, Miyazaki K, Imai H, Yokoe K, Ono R, Nosaka T, Katayama N.
  • Organizer: 56th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2014-12-06 – 2014-12-09
• [Presentation] パラインフルエンザウイルスのHNとFの機能的相互作用の分子機構： Fとの相互作用における HNのHead領域の役割. (2014)
  • Author(s): 鶴留雅人、伊藤守弘、大塚順平、駒田洋、西尾 真智子、野阪哲哉.
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: パシフィコ横浜会議センター
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] Analysis of novel molecular mechanisms leading to an aberrant self-renewal by Plzf in leukemogenesis. (2014)
  • Author(s): Ono R, Masuya M, Katayama N, Nosaka T.
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2014-10-31 – 2014-11-02
• [Remarks] 研究室ホームページ
  • URL: http://www.medic.mie-u.ac.jp/microbiol/