多方向かつ段階的に進行する細胞分化の運命決定メカニズムの解明

2014 Fiscal Year Annual Research Report

• Project Area: Molecular mechanisms of cell fate determination in the cells that undergo stepwise differentiation to multiple pathways
• Project/Area Number: 22118001
• Research Institution: The University of Tokyo
• Principal Investigator: 北村 俊雄 東京大学, 医科学研究所, 教授 (20282527)
• Co-Investigator(Kenkyū-buntansha): 河本 宏 京都大学, 再生医科学研究所, 教授 (00343228) ; 中西 真 名古屋市立大学, 医学(系)研究科(研究院), 教授 (40217774)
• Project Period (FY): 2010-04-01 – 2015-03-31
• Keywords: 細胞分化 / 細胞周期

Outline of Annual Research Achievements

第５回領域会議を９月２日から９月４日にかけて東京大学医科学研究所の講堂で一般公開の形式で開催し、計画班代表研究者、計画班分担研究者、公募班代表研究者が全員研究成果について口演を行い議論した。会期中に総括班会議を開催し、領域終了に向けて方針を相談した。
第２回若手の会を４月１８－１９日にかけて浜名湖グランドホテルにおいて開催した。参加者は計画研究代表者６名、招待講演の岩間教授（千葉大）に領域の若手を加えて４０名強で行なった。今回は招待演者の千葉先生には研究についての考え方、若手の独立研究者に独立までの道のりなどについて口演をお願いした。また、それぞれ若手の研究者にも自身の研究について口演あるいはポスターをお願いした。大いに盛り上がって素晴らしい会となった。
アウトリーチ活動として３つを行なった。まず例年通り、医科研における一般公開セミナー「エピジェネティクスって何？」を５月２２日に、また８月１０日には東京台場の日本科学未来館における「免疫ふしぎ未来」においてブースを出し、一般向けの解説をそれぞれ北村俊雄（領域代表）、河本宏（研究代表者）が行なった。
また、２月２０日には名古屋においてサイエンスカフェを開催し、稲葉俊哉（研究代表者）、中西真（研究代表者）、北村が、それぞれ低線量放射線障害、老化、エピジェネティクスについて一般向けの講演を行った。このサイエンスカフェは既に１００回近く続いている名古屋市大主催の予約制の一般公開セミナーであるが、今回は３名同時に講演するということもあり、定員の４０名がまたたく間に一杯になったと聞いている。講演会は多数の質問が出て熱気あふれるものとなった。後日、熱心な質問をメールで送ってきた人も複数あった。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] The stability of epigenetic factor ASXL1 is regulated through ubiquitination and USP7-mediated deubiquitination. (2015)
  • Author(s): Inoue, D., Nishimura, K., Kozuka-Hata, H., Oyama, M. and Kitamura, T.
  • Journal Title: Leukemia Volume: in press Pages: in press
  • DOI: 10.1038/leu.2015.90.
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Ceramido-CD300f binding suppresses experimental colitis by inhibiting ATP-mediated mast cell activation. (2015)
  • Author(s): Matsukawa, T., Izawa, K., Isobe, M., Takahashi, M., Maehara, A., Yamanishi, Y., Kaitani, A., Okumura, K., Teshima, T., *Kitamura, T. and *Kitaura, J.
  • Journal Title: Gut Volume: in press Pages: in press
  • DOI: 10.1136/gutjnl-2014-308900
  • Peer Reviewed
• [Journal Article] A C-terminal mutant of CCAAT-enhancer-binding protein α (C/EBPα-Cm) downregulates Csf1r, a potent accelerator in the progression of acute myeloid leukemia with C/EBPα-Cm (2015)
  • Author(s): Togami, K., Kitaura, J., Uchida, T., Inoue, D., Nishimura, K., Kawabata, K.C., Nagase, R., Horikawa, S., Izawa, K., Fukuyama, T., Nakahara, F., Oki, T., Harada, Y., Harada, H., Aburatani, H. and Kitamura, T.
  • Journal Title: Exp. Hematol. Volume: 43 Pages: 300-308
  • DOI: 10.1016/j.exphem.2014.11.011
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Autoimmune susceptible HLA alleles encode unstable proteins. (2015)
  • Author(s): Miyadera, H., Ohashi, J., Lernmark, A., Kitamura, T., and Tokunaga, K.
  • Journal Title: J. Clin. Invest. Volume: 125 Pages: 275-291
  • DOI: 10.1172/JCI74961.
  • Peer Reviewed
• [Journal Article] SETBP1 mutations drive leukemic transformation in ASXL1-murtated MDS. (2014)
  • Author(s): Inoue, D., Kitaura, J., Matsui, H., Hou, H-A, Chou, W-C, Nagamachi, A., Kawabata, K.C., Togami, K., Nagase, R., Horikawa, S., Saika, M., Micol, J-P., Hayashi, Y., Harada, Y., Harada, H., Inaba, T., Tien, H-F., Abdel-Wahab, O., and Kitamura, T.
  • Journal Title: Leukemia Volume: 29 Pages: 847-857
  • DOI: 10.1038/leu.2014.301
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The molecular basis of myeloid malignancies. (2014)
  • Author(s): Kitamura, T., Inoue, D., Okochi-Watanabe, N., Kato, N., Komeno, Y., Lu, Y., Enomoto, Y., Doki, N., Uchida, T., Kagiyama, Y., Togami, K., Kawabata, K.C., Nagase, R., Horikawa, S., Hayashi, Y., Saika, M., Fukuyama, T., Izawa, K., Oki, T., Nakahara, F., and Kitaura, J.
  • Journal Title: Proceedings of Japanese Acadmy, Series B Volume: 90 Pages: 389-404
  • DOI: 10.2183/pjab.90.389
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hes1 promotes blast crisis in chronic myelogenous leukemia through MMP-9 up-regulation in leukemic cells. (2014)
  • Author(s): Nakahara, F., Kitaura, J., Nishida, C., Uchida, T., Togami, K., Inoue, D., Matsukawa, T., Enomoto, Y., Kawabata, K.C., Chen-Yi, L., Komeno, Y., Izawa, K., Oki, T., Nagae, G., Harada, Y., Harada, H., Otsu, M., Aburatani, H., Hattori, K., and Kitamura, T.
  • Journal Title: Blood Volume: 123 Pages: 3932-3942
  • DOI: 10.1182/blood-2013-01-476747
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Ezh2 loss promotes development of myelodysplastic syndrome but attenuates its predisposition to leukemic transformation. (2014)
  • Author(s): Sashida, G., Harada, H., Matsui, H., Oshima, M., Yui, M., Harada, Y., Tanaka, S., Mochizuki-Kashio, M., Wang, C., Saraya, A., Muto, T., Hayasi, Y., Suzuki, K., Nakajima, H., Inaba, T., Koseki, H., Huang, G., Kitamura, T. and Iwama, A.
  • Journal Title: Nat. Commun. Volume: 5 Pages: 5177
  • DOI: 10.1038/ncomms5177
  • Peer Reviewed
• [Journal Article] Nov/CCN regulates long term repopulation activity of murine hematopietic stem cells via integrin αvβ3. (2014)
  • Author(s): Ishihara, J., Umemoto, T., Yamato, M., Shiratsuchi, Y., Takaki, S., Petrich, B.G., Nakauchi, H., Eto, K., Kitamura, T., and Okano T.
  • Journal Title: Int. J. Hematol. Volume: 99 Pages: 393-406
  • DOI: 10.1007/s12185-014-1534-x
  • Peer Reviewed
• [Journal Article] A novel cell-cycle indicator, mVenus-p27K-, identifies quiescent cells and visualizes G0-G1 transition. (2014)
  • Author(s): Oki, T., Nishimura, K., Kitaura, J., Togami, K., Maehara, A., Izawa, K., Sakaue-Sawano. A., Niida, A., Miyano, S., Aburatani, H., Kiyonari, H., Miyawaki, A. and Kitamura, T.
  • Journal Title: Scientific Reports Volume: 4 Pages: 4012
  • DOI: 10.1038/srep04012
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Hes1 up-regulation contributes to the development of FIP1L1-PDGFRA-positive leukemia in blast crisis. (2014)
  • Author(s): Uchida, T., Kitaura, J., Nakahara, F., Togami, K., Inoue, D., Maehara, A., Nishimura, K., Kawabata, C. K., Doki, N., Kakihana, K., Yoshioka, K., Izawa, K., Oki, T., Sada, A., Harada, Y., Ohashi, K., Katayama, Y., Matsui, T., Harada, H., and Kitamura, T.
  • Journal Title: Exp. Hematol. Volume: 42 Pages: 369-379
  • DOI: 10.1016/j.exphem.2014.01.009
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Age-related epigenetic drift in the pathogenesis of MDS and AML. (2014)
  • Author(s): Maegawa, S., Gough, S., Watanabe-Okochi, N., Lu, Y., Zhang, N., Castoro, R.J., Estecio, M.R.H., Jelinek, J., Liang, S., Kitamura, T., Aplan, P., and Issa, J.P.
  • Journal Title: Genome Research. Volume: 24 Pages: 580-591
  • DOI: 10.1101/gr.157529.113
  • Peer Reviewed
• [Journal Article] Sphingomyelin and ceramide are physiological ligands for human LMIR3/CD300f, inhibiting FceRI-mediated mast cell activation. (2014)
  • Author(s): Izawa, K., Isobe, M., Matsukawa, T., Ito, S., Maehara, A., Takahashi, M., Yamanishi, Y., Kaitani, A., Oki, T., Okumura, K., *Kitamura, T., and *Kitaura, J.
  • Journal Title: J. Allergy. Clin. Immunol. Volume: 133 Pages: 270-273
  • DOI: 10.1016/j.jaci.2013.08.008
  • Peer Reviewed
• [Journal Article] A promoter-level mammalian expression atlas. (2014)
  • Author(s): Forrest, A.R.R., Kawaji, H., Rehli, M., Baillie, J.K, de Hoon, M.J.L., Haberle, V., Lassmann, T., Kulakovskiy, I.V., Lizio, M., Itoh, M., Andersson, R., Mungall, C. J.,et al.
  • Journal Title: Nature Volume: 507 Pages: 462-470
  • DOI: 10.1038/nature13182
  • Peer Reviewed
• [Presentation] レトロウイルスベクターを利用した高効率遺伝子導入法とその応用 (2015)
  • Author(s): 北村俊雄
  • Organizer: 第１４回再生医療学会 シンポジウム
  • Place of Presentation: 横浜・パシフィコ横浜
  • Year and Date: 2015-03-21 – 2015-03-21
  • Invited
• [Presentation] Molecular basis by which mutations of epigenetic factors induce MDS-like symptons. (2015)
  • Author(s): K. Kawabata, D. Inoue and T. Kitamura.
  • Organizer: 日米造血器腫瘍学会
  • Place of Presentation: ハワイ島・米国
  • Year and Date: 2015-03-16 – 2015-03-18
  • Invited
• [Presentation] MDS induced by ASXL1 mutations and its leukemic transformation by an additional SETBP1 mutation (2015)
  • Author(s): D. Inoue, H. Matsui, T. Ochiya, F. Thol, M. Heuser, H-A How, W.C. Chou, J. Kitaura, R. Levine, H-F. Tien, O. Abdel-Wahab, T. Kitamura.
  • Organizer: キーストンシンポジウム
  • Place of Presentation: キーストン・米国
  • Year and Date: 2015-01-25 – 2015-01-30
• [Presentation] Molecular mechanisms of MDS and MDS/AML pathogenesis induced by ASXL1 and ASXL1/SETBP1 mutations. (2014)
  • Author(s): D. Inoue, T. Kitamura.
  • Organizer: 第４３回日本免疫学会
  • Place of Presentation: 京都・京都国際会館
  • Year and Date: 2014-12-10 – 2014-12-12
  • Invited
• [Presentation] MHC-peptide interaction analysis by the cell-surface expression assay. (2014)
  • Author(s): H.Miyadera, T.Kitamura, K.Tokunaga
  • Organizer: 第４３回日本免疫学会
  • Place of Presentation: 京都・京都国際会館
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] LMIR3/CD300f deficiency aggravates DSS-induced colitis. (2014)
  • Author(s): T.Matsukawa, K.Izawa, M.Isobe, M.Takahashi, A.Maehara, A.Kaitani, K.Okumura, T.Kitamura, J.Kitaura.
  • Organizer: 第４３回日本免疫学会
  • Place of Presentation: 京都・京都国際会館
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Secreted small RNAs regulate “inflammatory niche” and development of tumors. (2014)
  • Author(s): N.Yamakawa, K.Imadome, K.Hozumi, K.Ando, T.Kitamura, A.Kotani.
  • Organizer: 第４３回日本免疫学会
  • Place of Presentation: 京都・京都国際会館
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] isrupting ceramide-LMIR3 interaction prevents bacterial sepsis by stimulating neutrophil recruitment. (2014)
  • Author(s): K.Izawa, M.Isobe, T.Matsukawa, A.Maehara, M.Takahashi, A.Kaitani, K.Okumura, T.Kitamura, J.Kitaura.『Disrupting ceramide-LMIR3 interaction prevents bacterial sepsis by stimulating neutrophil recruitment.
  • Organizer: 第４３回日本免疫学会
  • Place of Presentation: 京都・京都国際会館
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] SETBP1 Mutations Drive Leukemic Transformation in ASXL1-Mutated MDS (2014)
  • Author(s): D.Inoue, H.Matsui, HA.Hou, WC.Chou, A.Nagamachi, J.Kitaura, K.Kawabata, K.Togami, R.Nagase, S.Horikawa, M.Saika, JB.Micol, Y.Hayashi, Y.Harada, HF.Tien, O.Abdel-Wahab, T.Kitamura.
  • Organizer: The 56th American Society of Hematology annual meeting
  • Place of Presentation: サンフランシスコ・アメリカ
  • Year and Date: 2014-12-08 – 2014-12-08
• [Presentation] MDS induced by ASXL1 mutations and its leukemic transformation by an additional SETBP1 mutation. (2014)
  • Author(s): D. Inoue and T. Kitamura.
  • Organizer: 日仏がんワークショップ
  • Place of Presentation: 京都・関西セミナーハウス
  • Year and Date: 2014-11-19 – 2014-11-21
• [Presentation] 骨髄系造血器腫瘍発症の分子機構 (2014)
  • Author(s): 北村俊雄
  • Organizer: 第７６回日本血液学会
  • Place of Presentation: 大阪・大阪国際会議場
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] C-terminal truncation type of RUNX1 mutants induce MDS/AML via gain-of-function mechanisms (2014)
  • Author(s): H.Harada, Y.Harada, D.Inoue, Y.Ding, G.Sashida, A.Iwama, H.Nakajima, J.Tanaka, N.Komatsu, T.Kitamura.
  • Organizer: 第７６回日本血液学会
  • Place of Presentation: 大阪・大阪国際会議場
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Dominant negative EZH2 promotes myeloid tumorigenesis in mouse BMT model. (2014)
  • Author(s): K.Kawabata, D.Inoue, J.Kitaura, T.Kitamura.
  • Organizer: 第７６回日本血液学会
  • Place of Presentation: 大阪・大阪国際会議場
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] SETBP1 mutations drive leukemic transformation in ASXL1-mutated MDS (2014)
  • Author(s): D.Inoue, J.Kitaura, K.Kawabata, H.Matsui, K.Togami, R.Nagase, S.Horikawa, T.Kitamura.
  • Organizer: 第７６回日本血液学会
  • Place of Presentation: 大阪・大阪国際会議場
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] ASXL1変異によるMDS・AML発症機構の解析 (2014)
  • Author(s): 井上大地
  • Organizer: 第130回小児血液腫瘍免疫懇話会
  • Place of Presentation: 東京・東京医科歯科大学
  • Year and Date: 2014-10-17 – 2014-10-17
• [Presentation] Molecular roles of ASXL1 mutations in inducing myelodysplastic syndromes. (2014)
  • Author(s): 北村俊雄
  • Organizer: 日本癌学会
  • Place of Presentation: 横浜・パシフィコ横浜
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] SETBP1 Mutations Drive Leukemic Transformation in ASXL1-Mutated MDS. (2014)
  • Author(s): D.Inoue.
  • Organizer: 43rd ISEH annual meeting.
  • Place of Presentation: モントリオール・カナダ
  • Year and Date: 2014-08-23 – 2014-08-23
• [Presentation] Modeling the hematological malignancies in mice. (2014)
  • Author(s): T. Kitamura.
  • Organizer: 43rd ISEH annual meeting.
  • Place of Presentation: モントリオール・カナダ
  • Year and Date: 2014-08-21 – 2014-08-24
  • Invited
• [Presentation] ASXL1変異によるMDS発症機構の解明 (2014)
  • Author(s): 井上大地・北村俊雄
  • Organizer: 第１０回麒麟塾
  • Place of Presentation: 東京 コクヨホール
  • Year and Date: 2014-07-10 – 2015-07-10
• [Presentation] C-terminal-truncating ASXL1 mutations induce MDS via repression of PRC2 function (2014)
  • Author(s): 井上大地・北村俊雄
  • Organizer: 平成26年度医科学研究所研究成果発表会
  • Place of Presentation: 東京 東京大学医科学研究所
  • Year and Date: 2014-05-31 – 2014-05-31
• [Presentation] MDS induced by ASXL1 mutations and its leukemic transformation by an additional SETBP1 mutation. (2014)
  • Author(s): T. Kitamura, D. Inoue, and J. Kitaura.
  • Organizer: Molecular Aspects of Myeloid Stem Cell Development and Leukemia.
  • Place of Presentation: シンシナティ・米国
  • Year and Date: 2014-05-04 – 2014-05-07
• [Presentation] Modeling hematological malignancies. (2014)
  • Author(s): T. Kitamura.
  • Organizer: Hematopoiesis meeting
  • Place of Presentation: ルンド・スウェーデン
  • Year and Date: 2014-04-24 – 2014-04-25
  • Invited