Molecular mechanism of MLL-related leukemogenesis in a mouse modelfor generation of cancer stem cells

• Project/Area Number: 22390206
• 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, 大学院・医学系研究科, 教授 (30218309)
• Co-Investigator(Kenkyū-buntansha): KITAMURA Toshio 東京大学, 医科学研究所, 教授 (20282527) ; ONO Ryoichi 三重大学, 大学院・医学系研究科, 講師 (40422414)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000); Fiscal Year 2012: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2011: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000); Fiscal Year 2010: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
• Keywords: 小児血液学 / 白血病幹細胞 / 白血病モデルマウス / MLL / 乳児白血病 / がん幹細胞 / 造血幹細胞 / PLZF

Research Abstract

We developed a transgenic mouse conditionally expressing an MLL chimeric gene which is frequently found in infantile and childfood leukemia patients. In this model system, leukemic stem cells were found to derive from only a hematopoieticstem cell population inducibly expressing MLL-ENL. PLZF gene was shown to play a pivotal role in development of MLL-ENL-mediated stem cell leukemia.

Research Products

• [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] 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: -
  • 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] IKAROS isoform 6 enhances BCR-ABL1-mediated proliferation of human CD34+ hematopoietic cells on stromal cells (2012)
  • Author(s): Suzuki K, et al
  • Journal Title: Int J Oncol Volume: 40 Pages: 53-62
  • DOI: 10.3892/ijo.2011.1192
  • 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- (2012)
  • Author(s): 野阪哲哉
  • Journal Title: 日本臨床 Volume: 70 Suppl 2 Pages: 159-164
• [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
• [Journal Article] Human parainfluenza virus type 2 L protein regions required for interaction with other viral proteins and mRNA capping. (2011)
  • Author(s): Nishio M, Tsurudome M, Garcin D, Komada H, Ito M, Le Mercier P, Nosaka T, Kolakofsky D.
  • Journal Title: J Virol Volume: 85 Issue: 2 Pages: 725-732
  • DOI: 10.1128/jvi.01226-10
  • Peer Reviewed
• [Journal Article] Identification of domains on the fusion (F) protein trimer that influence the hemagglutinin-neuraminidase specificity of the F protein in mediating cell-cell fusion. (2011)
  • Author(s): Tsurudome M, Ito M, Nishio M, Nakahashi M, Kawano M,Komada H, Nosaka T, Ito Y.
  • Journal Title: J Virol Volume: 85 Issue: 7 Pages: 3153-3161
  • DOI: 10.1128/jvi.01666-10
  • Peer Reviewed
• [Journal Article] Identification of domains on the fusion (F) protein trimer that influence the hemagglutinin-neuraminidase specificity of the F protein in mediating cell-cell fusion. (2011)
  • Author(s): Tsurudome M, Ito M, Nishio M, Nakahashi M, Kawano M, Komada H, Nosaka T, Ito Y.
  • Journal Title: J Virol Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Expression of ADAMTS4 in Ewing's sarcoma (2010)
  • Author(s): Minobe K, Ono R, Matsumine A, Shibata-Minoshima F, Izawa K, Oki T, Kitaura J, Iino T, Takita J, Iwamoto S, Hori H, Komada Y, Uchida A, Hayashi Y, Kitamura T, Nosaka T
  • Journal Title: Int J Oncol Volume: 37 Pages: 569-581
  • Peer Reviewed
• [Journal Article] MLL融合遺伝子による白血病発症機構 (2010)
  • Author(s): 野阪哲哉、小埜良一
  • Journal Title: 血液・腫瘍科 Volume: 61(2) Pages: 217-223
  • NAID: 40019064212
  • Peer Reviewed
• [Journal Article] Expression of ADAMTS4 in Ewing' s sarcoma. (2010)
  • Author(s): Minobe K, Ono R, Matsumine A, Shibata-Minoshima F, Izawa K, Oki T, Kitaura J, Iino T, Takita J, Iwamoto S, Hori H, Komada Y, Uchida A, Hayashi Y, Kitamura T, Nosaka T.
  • Journal Title: Int J Oncol Volume: 37 Pages: 569-581
  • Peer Reviewed
• [Journal Article] Cv2, functioning as a pro-BMP factor via twisted gastrulation, is required for early development of nephron precursors. (2010)
  • Author(s): Ikeya M, Fukushima K, Kawada M, Onishi S, Furuta Y, Yonemura S, Kitamura T, Nosaka T, Sasai Y.
  • Journal Title: Dev Biol Volume: 337 Pages: 405-414
  • Peer Reviewed
• [Journal Article] Plzf drives MLL-fusion-mediated leukemogenesis specifically in long term hematopoietic stem cells
  • Author(s): Ono R, Masuya M, Nakajima H, Enomoto Y, Miyata E, Nakamura A, Ishii S, Suzuki K, Shibata-Minoshima F, Katayama N, Kitamura T, Nosaka T
  • Journal Title: Blood
  • Peer Reviewed
• [Presentation] MLL fusion genes transform hematopoietic stem cells through an aberrant self-renewal program by Plzf (2012)
  • Author(s): Ono R, Masuya M, Nakajima H, Enomoto Y, Miyata E, Nakamura A, Ishii S, SuzukiK, 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
  • Year and Date: 2012-10-19
• [Presentation] Novel molecular mechanism of MLL-mediated leukemogenesis via a self-renewal transcription factor. (2011)
  • Author(s): Ono R, Masuya M, Nakajima H, Enomoto Y, Miyata E, Kamisako T, Ito M, NakamuraA, Suzuki K, Katayama N, Kitamura T, Nosaka T
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-15
• [Presentation] Differential role of PU.1 in leukemogenesis by HoxA9-Meis1 or MLL-fusion oncogene (2011)
  • Author(s): Fukuchi Y, Sadahira K, Kunimoto H, Sakurai M, Masuda A, Kawakita J, Ono R, Kitamura T, Nosaka T, Okamaoto S, Nakajima H
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-15
• [Presentation] Differential role of myeloid transcription factors, C/EBPa and PU.1 in Leukemogenesis by MLL-fusion oncogenes (2010)
  • Author(s): Fukuchi Y, Kuroda K, Sadahira K, Ono R, Tenen DG, KitamuraT, Nosaka T, Okamaoto S, Nakajima H
  • Organizer: 第52回アメリカ血液学会
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2010-12-04
• [Presentation] Differential role of myeloid transcription factors, C/EBPα and PU.1 in leukemogenesis by MLL-fusion oncogenes (2010)
  • Author(s): Fukuchi Y, Kuroda K, Sadahira K, Ono R, Tenen DG, Kitamura T, Nosaka T, Okamaoto S, Nakajima H.
  • Organizer: 第52回アメリカ血液学会
  • Place of Presentation: Orlando, FL, USA
  • Year and Date: 2010-12-04
• [Presentation] ヒトパラインフルエンザ2型ウイルス(hPIV2)L蛋白の転写能に必須であるアミノ酸の同定 (2010)
  • Author(s): 西尾真智子、鶴留雅人、野阪哲哉
  • Organizer: 第58回日本ウイルス学会学術集会
  • Place of Presentation: 徳島
  • Year and Date: 2010-11-08
• [Presentation] パラインフルエンザウイルスの膜融合誘導における受容体結合蛋白と膜融合蛋白の相互作用 (2010)
  • Author(s): 鶴留雅人、西尾真智子、伊藤守弘、河野光雄、野阪哲哉、駒田洋、伊藤康彦
  • Organizer: 第58回日本ウイルス学会学術集会
  • Place of Presentation: 徳島
  • Year and Date: 2010-11-08
• [Presentation] Ikaros isoform 6 enhances proliferative effect by BCR-ABL1 in human CD34+ hematopoietic cells (2010)
  • Author(s): Suzuki K, Ono R, Ohishi K, Kataoka I, Masuya M, HamadaH, Kitamura T, Katayama N, Nosaka T
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-26
• [Presentation] Differential role of C/EBPα and PU.1 in leukemogenesis by MLL-fusion oncogenes (2010)
  • Author(s): Fukuchi Y, Kuroda K, Sadahira K, Ono R, Ikeda Y, Kitamura T, Nosaka T, Okamaoto S, Nakajima H.
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2010-09-24
• [Presentation] Analysis of novel molecular mechanism in transformation by MLL-ENL targeting long-term hematopoietic stem cells (2010)
  • Author(s): Ono R, Masuya M, Nakajima H, Enomoto Y, Miyata E, Kamisako T, Ito M, Suzuki K, Katayama N, Kitamura T, Nosaka T
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-22
• [Presentation] Analysis of novel molecular mechanism in transformation by MLL-ENL targeting long-term hematopoietic stem cells. (2010)
  • Author(s): Ono R, Masuya M, Nakajima H, Enomoto Y, Miyata E, Kamisako T, Ito M, Suzuki K, Katayama N, Kitamura T, Nosaka T.
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
  • Year and Date: 2010-09-22
• [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, SuzukiK, 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
• [Presentation] Differential role of PU.1 in leukemogenesis by HoxA9-Meis1 or MLL-fusion oncogene.
  • Author(s): Fukuchi Y, Sadahira K, Kunimoto H, Sakurai M, Masuda A, Kawakita J, Ono R, Kitamura T, Nosaka T, Okamaoto S, Nakajima H.
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋
• [Presentation] Novel molecular mechanism of MLL-mediated leukemogenesis via a self-renewal transcription factor.
  • Author(s): Ono R, Masuya M, Nakajima H, Enomoto Y, Miyata E, Kamisako T, Ito M, Nakamura A, Suzuki K, Katayama N, Kitamura T, Nosaka T.
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋
• [Presentation] Identification of amino acids of Simian Virus 41 (SA41) fusion protein that convert Parainfluenza Virus 5 fusion protein to a protein which specifically interacts with SV41 Hemagglutinin-Neuraminidase by substitution.
  • Author(s): Tsurudome M, Nakahashi M, Matsushima Y, Nishio M, Kawano M, Komada H, Nosaka T.
  • Organizer: 第15回国際ウイルス学会学術集会（XV International Congress of Virology）
  • Place of Presentation: 札幌
• [Presentation] Nucleocytoplasmic shuttling of the human Parainfluenza Virus Type 2 Pprotein.
  • Author(s): Nishio M, Ohtsuka J, Tsurudome M, Nosaka T, Kolakofsky D.
  • Organizer: 第15回国際ウイルス学会学術集会（XV International Congress of Virology）
  • Place of Presentation: 札幌
• [Presentation] Ewing肉腫における新規腫瘍マーカーの探索：ADAMTS4発現の診断的意義の解析
  • Author(s): 美濃部こころ、松峯昭彦、小埜良一、飯野隆大、林泰秀、北村俊雄、内田淳正、須藤啓広、野阪哲哉
  • Organizer: 第26回日本整形外科学会基礎学術集会
  • Place of Presentation: 前橋
• [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 ホームページ
  • URL: http://www.medic.mie-u.ac.jp/microbiol/
• [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/
• [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/
• [Remarks]
  • URL: http://www.medic.mie-u.ac.jp/microbiol/