Integrative elucidation of molecular mechanisms for leukemogenesis: Identification and analyses of mutations with novel categories.

2013 Fiscal Year Final Research Report

• Project/Area Number: 23249051
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: The University of Tokyo
• Principal Investigator: KITAMURA Toshio 東京大学, 医科学研究所, 教授 (20282527)
• Co-Investigator(Kenkyū-buntansha): KITAURA Jiro 東京大学, 医科学研究所, 准教授 (30282651) ; NAKAHARA Fumio 東京大学, 医科学研究所, 助教 (80581181)
• Project Period (FY): 2011-05-31 – 2014-03-31
• Keywords: 血液腫瘍学

Research Abstract

Mutations in a variety of epigenetic factors have been recently identified in various hematological malignancies. We have demonstrated that the mutations in TET2, EZH2 or ASXL1 induce myelodysplastic syndromes (MDS)-like in mouse bone marrow transplant (BMT) model and that derepression of HoxA9 and miR125a induced by ASXL1 mutants via EZH2/PRC2 repression plays critical roles in inducing MDS-like disease.
We previously reported that Hes1 plays critical roles in CML-BC. We here demonstrate that MMP9 expression induced by Hes1 via NFkB activation plays some roles in the progression of CML-BC. In addition, we also demonstrated that Hes1 collaborated with FIP1L1-PDGFR in inducing AML in mouse BMT model and that Hes1 overexpression was observed in 2 of 5 patients with eosinophilic leukemia harboring FIP1L1-PDGFR. These results indicate that Hes1 contribute to leukemogenesis in suppressing myeloid differentiation.

Research Products

• [Journal Article] 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 (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: (in press)
  • DOI: 10.1182/blood-2013-01-476747
• [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: Nature Commun Volume: (in press)
  • URL: http://www.nature.com/ncomms/index.html
• [Journal Article] Nov/CCN regulates long term repopulation activity of murine hematopietic stem cells via integrin avb3 (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
• [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: (in press)
  • DOI: 10.1016/j.exphem.2014.01.009
• [Journal Article] Myelodysplastic syndromes are induced by histone methylation-altering ASXL1 mutations (2013)
  • Author(s): Inoue, D., Kitaura, J., Togami, K., Nishimura, K., Enomoto, Y., Uchida, T., Kagiyama, Y., Kawabata, K. C., Nakahara, F., Izawa, K., Oki, T., Maehara, A., Isobe, M., Tsuchiya, A., Harada, Y., Harada, H., Ochiya, T., Aburatani, A., Kimura, H., Thol, F., Heuser, M., Levine, R. L., Abdel-Wahab, O. and Kitamura, T
  • Journal Title: J. Clin. Invest Volume: 123 Pages: 4627-4640
  • DOI: 10.1172/JCI70739
• [Journal Article] The shortest isoform of C/EBPβ, Liver inhibitory protein (LIP) , collaborates with Evi1 to induce AML in a mouse BMT model (2013)
  • Author(s): Okochi, N., Yoshimi, A., Sato, T., Ikeda, T., Kumano, K., Taoka, K., Sato, Y., Shinohara, A., Tsuruta, A., Masuda, A., Yokota, H., Yatomi, Y., Takahashi, K., Kitaura, J., Kitamura, T. and Kurokawa, M
  • Journal Title: Blood Volume: 121 Pages: 4142-4155
  • DOI: 10.1182/blood-2011-07-368654
• [Journal Article] Runx1/AML1 mutant collaborates with Bmi1 overexpression in the development of human and mouse myelodysplastic syndromes (2013)
  • Author(s): Harada, Y., Inoue, D., Ding, Y., Imagawa, J., Doki, N., Matsui, H., Yahata, T., Matsushita, H., Ando, K., Shashida, G., Iwama, A., Kitamura, T. and Harada, H
  • Journal Title: Blood Volume: 13 Pages: 3434-3446
  • DOI: 10.1182/blood-2012-06-434423
• [Journal Article] MicroRNA-125b-1 accelerates a C-terminal mutant of C/EBPa (C/EBPa-C(m)) -induced myeloid leukemia (2012)
  • Author(s): Enomoto, Y., Kitaura, J., Shimanuki, M., Kato, N., Nishimura, K., Takahashi, M., Nakamura, H., Kitamura, T., and Sonoki T
  • Journal Title: Int. J. Hematol Volume: 96 Pages: 334-341
  • DOI: 10.1007/s12185-012-1143-5
• [Journal Article] Aberrant expression of RasGRP1 cooperates with gain-of-function NOTCH1 mutations in T-cell leukemogenesis (2012)
  • Author(s): Oki, T., Kitaura, J., Watanabe-Okochi, N., Nishimura, K., Maehara, A., Uchida, T., Komeno, Y., Nakahara, F., Harada, Y., Sonoki, T., Harada, H., and Kitamura, T.
  • Journal Title: Leukemia Volume: 26 Pages: 1038-1045
  • DOI: 10.1038/leu.2011.328
• [Journal Article] E□/miR-125b transgenic mice develop lethal B-cell malignancies (2011)
  • Author(s): Enomoto, Y., Kitaura, J., Hatakeyama, K., Watanuki, J., Akasaka, T., Kato, N., Shimanuki, M., Nishimura, K., Takahashi, M., Taniwaki, M., Haferlach, C., Siebert, S., Dyer, M. J. S., Asou, N., Nakakuma, H., Kitamura, T., and Sonoki, T
  • Journal Title: Leukemia Volume: 25 Pages: 1849-1856
  • DOI: 10.1038/leu.2011.166
• [Journal Article] Two types of C/EBPa mutations play distinct roles in leukemogenesis : Lessons from clinical data and BMT models (2011)
  • Author(s): Kato, N., Kitaura, J., Doki, N., Komeno, Y., Watanabe-Okochi N., Togami, K., Nakahara, F., Oki, T., Enomoto, Y., Fukuchi, Y., Nakajima, H., Harada, Y., Harada, H., and Kitamura. T
  • Journal Title: Blood Volume: 117 Pages: 221-233
  • DOI: 10.1182/blood-2010-02-270181
• [Presentation] C-terminal-truncating ASXL1 mutations induce MDS via repression of PRC2 function (2013)
  • Author(s): 井上大地, 北村俊雄
  • Organizer: The 55th American Society of Hematology annual meeting
  • Place of Presentation: ニューオーリンズ
  • Year and Date: 2013-12-09
• [Presentation] Hes1 promotes blast crisis of chronic myelogenous leukemia through MMP-9 up-regulation (2013)
  • Author(s): 北村俊雄
  • Organizer: 分子生物学会ワークショップ
  • Place of Presentation: 神戸
  • Year and Date: 2013-12-04
• [Presentation] ASXL1 mutations induces an MDS-like disease in mice via derepression of HoxA9 and miR125a (2013)
  • Author(s): 北村俊雄
  • Organizer: 日仏がん会議(French Japanese Cancer Meeting)
  • Place of Presentation: トゥールーズ
  • Year and Date: 2013-11-21
  • Invited
• [Presentation] Molecular aspects of leukemic transformation of myelodysplastic syndromes (MDS) and myeloproliferative neoplasm (MPN) (2012)
  • Author(s): Toshio Kitamura
  • Organizer: 日仏がんワークショップ
  • Place of Presentation: 徳島グランドエクシブ鳴門
  • Year and Date: 20121129-1201
  • Invited
• [Presentation] Leukemogenesis induced by C-terminal mutations in the basic leucine zipper domain of C/EBPα (2012)
  • Author(s): 戸上勝仁, 北浦次郎, 井上大地, 鍵山侑希, 内田智之, 西村耕太郎, 土岐典子, 加藤菜穂子, 中原史雄, 沖俊彦, 原田結花, 原田浩徳, 北村俊雄
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都国際会館
  • Year and Date: 2012-10-20
• [Presentation] Molecular Mechanisms of blast crisis in chronic myelogenous leukemia caused by upregulation of Hes1 (2012)
  • Author(s): 中原史雄, 北浦次郎, 川畑公人, 内田智之,鍵山侑希, 井上大地, 戸上勝仁, 沖俊彦, 原田結花 , 原田浩徳 , 北村俊雄
  • Organizer: 第74回日本血液学会
  • Place of Presentation: 京都国際会館
  • Year and Date: 2012-10-20
• [Presentation] Molecular basis of leukemia, MPN and MDS (2011)
  • Author(s): 北村俊雄
  • Organizer: 第70回日本癌学会学術総会シンポジウム
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 20111103-05
• [Presentation] Mouse models for MDS/overt leukemia and CML-BC (2011)
  • Author(s): 北村俊雄
  • Organizer: 第73回日本血液学会学術集会シンポジウム
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 20111014-16
• [Presentation] Two types of C/EBPa mutations collaborate in inducing leukemia in a mouse BMT model (2011)
  • Author(s): 北村俊雄
  • Organizer: 第25回IACRLRD
  • Place of Presentation: 東京大学本郷キャンパス
  • Year and Date: 20110915-17
• [Presentation] Lessons from mouse models for myelodysplastic syndromes/overt leukemia and chronic myelogeneous leukemia in blast crisis : Insertional mutagenesis induced Evi-1 expression but not Hes1 expression (2011)
  • Author(s): 北村俊雄
  • Organizer: 日本学術振興会二国間交流事業セミナー
  • Place of Presentation: 九州大学百年講堂
  • Year and Date: 2011-07-14
• [Presentation] Animal models for AML (2011)
  • Author(s): 北村俊雄
  • Organizer: MDS and MPN 日本遺伝子治療学会教育講演
  • Place of Presentation: 九州大学百年講堂
  • Year and Date: 2011-07-14
• [Remarks]
  • URL: http://www.ims.u-tokyo.ac.jp/clinical_oncol/