ＥＶＩ１は造血及び神経幹細胞の運命を制御する

• Project Area: Molecular mechanisms of cell fate determination in the cells that undergo stepwise differentiation to multiple pathways
• Project/Area Number: 23118523
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: University of Miyazaki
• Principal Investigator: 森下 和広 宮崎大学, 医学部, 教授 (80260321)
• Project Period (FY): 2011-04-01 – 2013-03-31
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000); Fiscal Year 2012: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2011: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 発生分化 / 造血 / 神経 / 分化 / EVI1

Outline of Annual Research Achievements

Ecotropic viral integration site-1(Evi1)遺伝子は3番染色体q26領域のゲノム異常(3q21q26症候群)を含む成人骨髄性白血病（AML）の7-10％で高発現する予後不良因子として知られて来ている。EVI1発現は神経及び造血の器官形成運命決定過程関わる鍵因子となる可能性を有すため、この研究では神経幹細胞におけるEVI1発現を検討した。その結果Neural sphere(神経幹細胞)においてEVI1の発現が見られるが、細胞分化により発現低下し、神経細胞系での発現が保たれた。またEvi1ヘテロ欠損マウスにおいてNeural sphereにおいて神経細胞分化の抑制と、星状細胞への分化促進が見られた。同時にNotch情報伝達系の抑制傾向が見られたため、Neural sphere にEVI1強制発現するとはHes1高発現、Notch情報伝達系の促進が有り神経細胞分化との関連が示唆された。さらに、Evi1ヘテロ欠損マウスにおいては、神経突起の進展が阻害されることから、shEvi1導入し神経細胞分化を起こさせると同様に神経突起進展阻害が見られた。神経突起におけるEvi1の発現は細胞質に存在するため、転写調節とは別の機能が存在すると考えられる。一方でEvi1の標的遺伝子として同定した神経幹細胞維持に関わるGPR56はGpr56欠損マウスの検討から、造血幹細胞維持にも重要な因子であることが分かった。従って、EVI1は神経並びに造血神経器官形成や細胞の分化運命決定過程に関して重要な働きを有しており、神経並びに造血系におけるさらなる比較検討が必要である。

Research Progress Status

24年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

24年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Maintenance of the hematopoietic stem cell pool in bone marrow niches by EVI1-regulated GPR56 (2013)
  • Author(s): Saito Y., Kaneda K., Suekane A., Ichihara E., Nakahata S., Yamakawa N., Nagai K., Mizuno N., Kogawa K., Miura I., Itoh H., and Morishita K..
  • Journal Title: Leukemia Volume: 27 Issue: 8 Pages: 1637-1649
  • DOI: 10.1038/leu.2013.75
  • Peer Reviewed
• [Journal Article] Angiopoietinl contributes to the maintenance of cell quiescence in EVI1 high leukemia cells (2011)
  • Author(s): Emi Ichihara
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 416 Issue: 3-4 Pages: 239-245
  • DOI: 10.1016/j.bbrc.2011.10.061
  • Peer Reviewed
• [Journal Article] Sumoylation of MEL1S at lysine 568 and its interaction with CtBP facilitates its repressor activity and the blockade of G-CSF-induced myeloid differentiation (2011)
  • Author(s): Nishikata I, Nakahata S, Saito Y, Kaneda K, Ichihara E, Yamakawa N, and Morishita K
  • Journal Title: Oncogene Volume: 30 Issue: 40 Pages: 196-207
  • DOI: 10.1038/onc.2011.132
  • Peer Reviewed
• [Journal Article] CD52 as a molecular target for immunotherapy to treat acute myeloid leukemia with high EVI1 expression (2011)
  • Author(s): Saito Y, Nakahata S, Yamakawa N, Kaneda K, Ichihara A, Suekane A, and Morishita K
  • Journal Title: Leukemia Volume: 25 Issue: 6 Pages: 921-931
  • DOI: 10.1038/leu.2011.36
  • Peer Reviewed
• [Journal Article] GluA4 is Indispensable for Driving Fast Neurotransmission across a High-fidelity Central Synapse. J Physiol (2011)
  • Author(s): Yang, Y.M., Aitoubah, J., Lauer, A.M., Nuriya, M., Takamiya, K., Jia, Z., May, B.J., Huganir, R.L., Wang, L.Y.
  • Journal Title: J Physiol Volume: 589 Issue: 17 Pages: 4209-27
  • DOI: 10.1113/jphysiol.2011.208066
  • Peer Reviewed
• [Journal Article] Preserved acute pain and impaired neuropathic pain in mice lacking protein interacting with C Kinase 1 (2011)
  • Author(s): Wang, W., Petralia, R.S., Takamiya, K., Xia, J., Li, Y.Q., Huganir, R.L., Tao, Y.X., Yaster, M
  • Journal Title: Molecular pain Volume: 7 Pages: 11-11
  • DOI: 10.1186/1744-8069-7-11
  • Peer Reviewed
• [Journal Article] Reevaluating the Role of LTD in Cerebellar Motor Learning (2011)
  • Author(s): Schonewille, M., Gao, Z., Boele, H.J., Vinueza Veloz, M.F., Amerika, W.E., Simek, A.A., De Jeu, M.T., Steinberg, J.P., Takamiya, K., Hoebeek, F.E., et al
  • Journal Title: Neuron Volume: 71 Issue: 1 Pages: 43-50
  • DOI: 10.1016/j.neuron.2011.02.044
  • Peer Reviewed
• [Journal Article] Regulation of AMPA receptor function by the human memory-associated gene KIBRA (2011)
  • Author(s): Makuch, L., Volk, L., Anggono, V., Johnson, R.C., Yu, Y., Duning, K, Kremerskothen, J., Xia, J., Takamiya, K, Huganir, R.L.
  • Journal Title: Neuron Volume: 71 Issue: 6 Pages: 1022-1029
  • DOI: 10.1016/j.neuron.2011.08.017
  • Peer Reviewed
• [Journal Article] Enhanced synaptic plasticity in mice with phosphomimetic mutation of the GluA1 AMPA receptor (2011)
  • Author(s): Makino, Y., Johnson, R.C., Yu, Y., Takamiya, K., Huganir, R.L.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 108 Issue: 20 Pages: 8450-8455
  • DOI: 10.1073/pnas.1105261108
  • Peer Reviewed
• [Journal Article] Phosphorylation of AMPA receptors is required for sensory deprivation-induced homeostatic synaptic plasticity (2011)
  • Author(s): Goel, A., Xu, L.W., Snyder, K.P., Song, L., Goenaga-Vazquez, Y., Megill, A., Takamiya, K., Huganir, R.L., Lee, H.K.
  • Journal Title: PLoS One Volume: 6 Issue: 3 Pages: 1016-1026
  • DOI: 10.1371/journal.pone.0018264
  • Peer Reviewed
• [Presentation] Maintenance of the the hematophoietic stem cell pool in bone marrow niches by EVI1-regulated GPR56. (2012)
  • Author(s): 斎藤祐介
  • Organizer: 第74回日本血液学会学術集会
  • Place of Presentation: 京都市左京区.
  • Year and Date: 2012-10-19
  • Invited
• [Presentation] odulation of drug-resistance derived from high expression of ITGA6 and ITGB4 via EVI1 in leukemia cell lines (2011)
  • Author(s): Kaneda-Nakashima K.
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-15
• [Presentation] Maintenance of the hematopoietic stem cell pool by GPR56 signaling in bone marrow stromal cell niches (2011)
  • Author(s): Saito Y.
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2011-12-13
• [Presentation] GPR56 integrate signals regulating HSC and EVI1 high AML niche interaction in the bone marrow (2011)
  • Author(s): Saito Y.
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋市熱田区
  • Year and Date: 2011-10-14
• [Presentation] Autocrine angiopoietin-1/Tie2 signaling promotes cell quiescence in EVI1^<high> leukemia cells (2011)
  • Author(s): Ichihara E.
  • Organizer: 第73回日本血液学会学術集会
  • Place of Presentation: 名古屋市熱田区
  • Year and Date: 2011-10-14
• [Presentation] EVI1高発現白血病細胞において自己分泌型Ang1/Tie2シグナル亢進は細胞周期を負に制御している (2011)
  • Author(s): 市原絵美
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都府左京区
  • Year and Date: 2011-09-22
• [Patent(Industrial Property Rights)] 細胞接着阻害剤、細胞増殖阻害剤、並びに癌の検査方法および検査用キット (2012)
  • Inventor(s): 森下和広 斎藤祐介
  • Industrial Property Rights Holder: 森下和広 斎藤祐介
  • Industrial Property Rights Type: 特許
  • Filing Date: 2012-05-11
  • Overseas
• [Patent(Industrial Property Rights)] 細胞接着阻害剤、細胞増殖阻害剤、並びに癌の検査方法および検査用キット (2011)
  • Inventor(s): 森下和広、齋藤祐介
  • Industrial Property Rights Holder: 宮崎大学
  • Filing Date: 2011-11-09