Model for generation of leukemic stem cells: spatio-temporal properties in pathogenesis

• Project/Area Number: 24659494
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• 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): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 白血病 / 白血病幹細胞 / ＭＬＬ / ＭＬＬ－ＥＮＬ / MLL / MLL-ENL / マウスモデル

Outline of Final Research Achievements

The goal of this study is to clarify the molecular mechanism for generation of leukemic stem cells by using the inducible MLL-ENL transgenic mice which we made.
The efficiency of immortalization of fetal liver cells was lower than that of adult bone marrow cells when MLL-ENL was inducibly expressed. In addition, we found that Tet1 which is known to be involved in self renewal of embryonic stem cells, negatively regulates the leukemogenesis in this model system.

Research Products

• [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
• [Journal Article] Plzf drives MLL-fusion-mediated leukemogenesis specifically in long-term hematopoietic stem cells. (2013)
  • Author(s): Ono, R
  • Journal Title: Blood Volume: 122 Issue: 7 Pages: 1271-1283
  • DOI: 10.1182/blood-2012-09-456665
  • Peer Reviewed
• [Journal Article] Manipulation of human early T lymphopoiesis by coculture on human bone marrow stromal cells: Potential utility for adoptive immunotherapy (2013)
  • Author(s): Liu B, Ohishi K, Orito Y,N a k a mo r i Y, Nishikawa H, Ino K,Suzuki K, Matsumoto T,Masuya M,Hamada H, Mineno J, Ono R, Nosaka T, Shiku H, Katayama N.
  • Journal Title: Exp Hematol Volume: - Issue: 4 Pages: 367-376
  • DOI: 10.1016/j.exphem.2012.12.001
  • Peer Reviewed
• [Journal Article] Full conversion of the hemagglutinin-neuraminidase specificity of the parainfluenza virus 5 fusion protein by replacement of 21 amino acids in its head region with those of the simian virus 41 fusion protein. (2013)
  • Author(s): Tsurudome M, Nakahashi M, Matsushima Y, Ito M, Nishio M, Kawano M, Komada H, Nosaka T.
  • Journal Title: J. Virol. Volume: 87 Issue: 15 Pages: 8342-8350
  • DOI: 10.1128/jvi.03549-12
  • Peer Reviewed
• [Journal Article] Intranasally administered antigen 85B gene vaccine in non-replicating human Parainfluenza type 2 virus vector ameliorates mouse atopic dermatitis. (2013)
  • Author(s): Kitagawa H, Kawano M, Yamanaka K, Kakeda M, Tsuda K, Inada H, Yoneda M, Sakaguchi T, Nigi A, Nishimura K, Komada H, Tsurudome M, Yasutomi Y, Nosaka T, Mizutani H.
  • Journal Title: PLoS One. Volume: 8 Issue: 7 Pages: 66614-66614
  • DOI: 10.1371/journal.pone.0066614
  • Peer Reviewed
• [Journal Article] Human Parainfluenza virus type 2 vector induces dendritic cell maturation without viral RNA replication/transcription. (2013)
  • Author(s): Hara K, Fukumura M, Ohtsuka J, Kawano M, Nosaka T.
  • Journal Title: Hum Gene Ther Volume: 24 Issue: 7 Pages: 683-691
  • DOI: 10.1089/hum.2013.024
  • Peer Reviewed
• [Journal Article] Cynomolgus monkey induced pluripotent stem cells established by using exogenous genes derived from the same monkey species. (2013)
  • Author(s): Shimozawa N, Ono R, Shimada M, Shibata H, Takahashi I, Inada H, Takada T, Nosaka T, Yasutomi Y.
  • Journal Title: Differentiation Volume: 85 Issue: 4-5 Pages: 131-139
  • DOI: 10.1016/j.diff.2013.02.004
  • Peer Reviewed
• [Journal Article] High resolution melting curve assay for rapid detection of drug-resistant Mycobacterium tuberculosis. (2013)
  • Author(s): Nagai Y, Iwade Y, Hayakawa E, Nakano M, Sakai T, Mitarai S, Katayama M, Nosaka T, Yamaguchi T.
  • Journal Title: J Infect Chemother Volume: 19 Issue: 6 Pages: 1116-1125
  • DOI: 10.1007/s10156-013-0636-3
  • Peer Reviewed
• [Journal Article] Regulation of AMP-activated Protein Kinase Signaling by AFF4, a Member of the AF4 (ALL1-fused Gene from Chromosome 4) Family of Transcription Factors, in Hypothalamic Neurons (2012)
  • Author(s): Komori T, Doi A, Nosaka T, Furuta H, Akamizu T, Kitamura T, Senba E, Morikawa Y.
  • Journal Title: J Biol Chem Volume: 287 Issue: 24 Pages: 19985-19996
  • DOI: 10.1074/jbc.m112.367854
  • Peer Reviewed
• [Journal Article] Molecular genotyping of Mycobacterium tuberculosis in Mie Prefecture, Japan, using variable numbers of tandem repeats analysis. (2012)
  • Author(s): Nagai Y, Iwade Y, HayakawaE, Nakano M, Sakai T, Tanuma M, Katayama M, Nosaka T, Yamaguchi T.
  • Journal Title: Jpn J Infect Dis Volume: 65 Pages: 341-344
  • NAID: 130001931836
  • Peer Reviewed
• [Journal Article] 血液腫瘍モデル動物の現状と展望. (2012)
  • Author(s): 野阪哲哉.
  • Journal Title: In: 金倉譲 編集. 造血器腫瘍学-基礎と臨床の最新研究動向- 日本臨床 Volume: 70卷 増刊号2 Pages: 159-164
• [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
• [Presentation] MLL融合遺伝子による造血幹細胞の癌化にはPlzfを介した異常な自己複製機構が重要である (2013)
  • Author(s): 小埜良一、野阪哲哉
  • Organizer: 第65回日本細胞生物学会大会
  • Place of Presentation: ウインクあいち
• [Presentation] Conversion of the parainfluenza virus 5 F protein to a simian virus 41 HN-specific protein by amino acid substitutions (2013)
  • Author(s): Tsurudome M, Ito M, Nishio M, Nosaka T
  • Organizer: 15th International Negative Strand Virus Meeting
  • Place of Presentation: Granada, Spain
• [Presentation] パラインフルエンザウイルスのHN蛋白とF蛋白の機能的相互作用の解析 (2013)
  • Author(s): 鶴留雅人、伊藤守弘、西尾真智子、河野光雄、駒田洋、大塚順平、野阪哲哉
  • Organizer: 第61回日本ウイルス学会学術集会
  • Place of Presentation: 神戸国際会議場
• [Presentation] MLL fusion genes transform hematopoietic stem cells through an aberrant self-renewal program by Plzf.
  • Author(s): Ono R, Masuya M, Nakajima H, Enomoto Y, Miyata E, Nakamura A, Ishii S, Suzuki K, Katayama N, Kitamura T, Nosaka T.
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都
• [Presentation] パラミクソウイルスの膜融合誘導機構：二分子蛍光相補性（BiFC）法を用いた受容体結合蛋白と膜融合蛋白の相互作用の解析
  • Author(s): 鶴留雅人、大塚順平、駒田洋、河野光雄、伊藤守弘、野阪哲哉
  • Organizer: 第60回日本ウイルス学会学術集会
  • Place of Presentation: 大阪
• [Remarks] ホームページ
  • URL: http://www.medic.mie-u.ac.jp/microbiol/index.html
• [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/