Identification of microRNAs regulating apoptosis and elucidation of their roles in tumorigenesis

• Project/Area Number: 23790622
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Laboratory medicine
• Research Institution: Osaka University
• Principal Investigator: TATSUMI Naoya 大阪大学, 大学院・医学系研究科, 寄附講座助教 (60512960)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2011: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: microRNA / WT1 遺伝子 / 骨髄増殖性疾患 / WT1 / WT1遺伝子 / ノックアウトマウス

Research Abstract

The Wilms’ tumor gene WT1 is overexpressed and plays an oncogenic role in themajority of human leukemia and various types of solid tumors. Therefore, it is important to identify the molecular mechanism by which WT1 is overexpressed to understand their roles in tumorigenesis. In the present study, we identified microRNA-A (miR-A) as a miRNA that repressed WT1 expression by its binding to the WT1-3’UTR. miR-A-deficient mice exhibited high expression of WT1 in hematopoietic stem/progenitor cells (HSPCs) and developed myeloproliferative disorders (MPDs) characterized by expansion of myeloid cells in the BM, spleen and peripheral blood. Furthermore, silencing of WT1 expression in HSPCs of MPD miR-A-deficient mice by short hairpin RNA inhibited myeloid proliferation and differentiation in vitro. These results indicate that loss or decreased expression of miR-A plays an important role in the development of MPD through dysregulated overexpression of WT1 in HSPCs.

Research Products

• [Journal Article] HLA-DPB1*05: 01-restricted WT1332-specific TCR-transduced CD4+ T lymphocytes display a helper activity for WT1-specific CTL induction and a cytotoxicity against leukemia cells. (2013)
  • Author(s): Lin Y, Fujiki F, Katsuhara A, Oka Y, Tsuboi A, Aoyama N, Tanii S, Nakajima H, Tatsumi N, Morimoto S, Tamanaka T, Tachino S, Hosen N, Nishida S, Oji Y, Kumanogoh A, Sugiyama H.
  • Journal Title: J Immunother. Volume: 36（3） Issue: 3 Pages: 159-70
  • DOI: 10.1097/cji.0b013e3182873581
  • Peer Reviewed
• [Journal Article] CD138-negative clonogenic cells are plasma cells but not B cells in some multiple myeloma patients (2012)
  • Author(s): Hosen N, Matsuoka Y, Kishida S, Nakata J, Mizutani Y, Hasegawa K, Mugitani A, Ichihara H, Aoyama Y, Nishida S, Tsuboi A, Fujiki F, Tatsumi N, Nakajima H, Hino M, Kimura T, Yata K, Abe M, Oka Y, Oji Y, Kumanogoh A, Sugiyama H.
  • Journal Title: Leukemia Volume: (in press) Issue: 9 Pages: 2135-2141
  • DOI: 10.1038/leu.2012.80
  • Peer Reviewed
• [Journal Article] Enhanced tumor immunity of WT1 peptide vaccination by interferon-β administration (2012)
  • Author(s): Nakajima H., et al
  • Journal Title: Vaccine Volume: 30 Issue: 4 Pages: 722-729
  • DOI: 10.1016/j.vaccine.2011.11.074
  • Peer Reviewed
• [Presentation] HLA cass II-restricted WT1 332-specific TCR-transduced CD4+ T lymphocytes display a helper activity for WT1-specific CTL induction and cytotoxicity against leukemia cells (2012)
  • Author(s): Yuhung Lin, Fumihiro Fujiki, Akiko Katsuhara, Yoshihiro Oka, Akihiro Tsuboi, Nao Aoyama, Satoe Tanii, Hiroko Nakajima, Naoya Tatsumi, Soyoko Morimoto, Taichi Tamanaka, Sho Tachino, Naoki Hosen, Sumiyuki Nishida, Yusuke Oji, Atsushi Kumanogoh and Haruo Sug
  • Organizer: 第6回国際 WT1 会議
  • Place of Presentation: 京都
  • Year and Date: 2012-11-23
• [Presentation] Wilms tumo 1 (WT1) peptide vaccine as an enhancer of graft versus leukemia effects (2012)
  • Author(s): Naoki Hosen, Tetsuo Maeda, Kentaro Fukushima, Soyoko Morimoto, Jun Nakata, Yoshiki Nakae, Satoshi Takashima, Hiroko Nakajima, Fumihiro Fujiki, Naoya Tatsumi, Sumiyuki Nishida, Akihiro Tsuboi, Tadakazu Kondo, Masayuki Hino, Yusuke Oji, Yoshihiro Oka, Atsus
  • Organizer: 第6回国際 WT1 会議
  • Place of Presentation: 京都
  • Year and Date: 2012-11-23
• [Presentation] International harmonization on immunohistochemical evaluation of WT1 positivity in solid cancer (2012)
  • Author(s): Y usuke Oji, Zwi N. Berneman, UlrichKeilholz, Richard O'reilly, Giuseppe Saglio, Nicole Wargner, Yuji Heike, Eva Lundin, Eiichi Morii, Patrick Pauwels, Mauro Pappotti, Sebastien Aanguille, Daniela Cilloni, Anne Letsch, Hiroshi Ohashi, Yuko Ohno, Wim Waelp
  • Organizer: 第6回国際 WT1会議
  • Place of Presentation: 京都
  • Year and Date: 2012-11-22
• [Presentation] 固形癌における WT1 発現の免疫組織化学法による評価 (2012)
  • Author(s): 尾路祐介、福田茉莉、森井英一、 辰巳直也、北條望、村上由依、斉藤千紗恵、鈴木望友、川田紗世、澄川美穂子、坪井昭博、岡芳弘、杉山治夫
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Year and Date: 2012-09-21
• [Presentation] 慢性期 CML に対するイマチニブ併用 WT1 ペプチドワクチン免疫療法 (2012)
  • Author(s): 尾路祐介、岡芳弘、坪井昭博、保仙直毅、西田純幸、中田潤、中江吉希、中島博子、藤木文博、辰巳直也、杉山治夫
  • Organizer: 第4回造血器腫瘍免疫療法研究会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2012-08-18
• [Presentation] WT1 ヘルパーペプチド投与による抗腫瘍免疫反応の増強-マウスモデルを用いた検討- (2012)
  • Author(s): 中島博子、岡芳弘、坪井昭博、藤木文博、辰巳直也、尾路祐介、杉山治夫
  • Organizer: 第4回造血器腫瘍免疫療法研究会学術集会
  • Place of Presentation: 金沢
  • Year and Date: 2012-08-18
• [Presentation] IFN-β併用投与による WT1 ペプチドワクチンの腫瘍拒絶効果の増強 (2011)
  • Author(s): 中島博子、岡芳弘、坪井昭博、辰巳直也、藤木文博、森本創世子、保仙直毅、白方俊章、西田純幸、尾路祐介、杉山治夫
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-04
• [Presentation] IFN-β併用投与による WT1 ペプチドワクチンの造血器腫瘍に対する拒絶効果の増強 (2011)
  • Author(s): 中島博子、岡芳弘、坪井昭博、辰巳直也、藤木文博、保仙直毅、西田順幸、尾路祐介、杉山治夫
  • Organizer: 第3回造血器腫瘍免疫療法研究会学術集会
  • Place of Presentation: 大分
  • Year and Date: 2011-08-20
• [Presentation] IFN-ベータ併用投与によるWT1ペプチドワクチンの腫瘍拒絶効果の増強 (2011)
  • Author(s): 中島博子
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場
• [Presentation] 固形癌におけるWT1発現の免疫組織化学法による評価
  • Author(s): 尾路祐介
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Remarks] 大阪大学大学院医学系研究科 機能診断科学講座 免疫造血制御学研究室
  • URL: http://sahswww.med.osaka-u.ac.jp/~hmtonc/index.html
• [Remarks]
  • URL: http://sahswww.med.osaka-u.ac.jp/~hmtonc/index.html