Establishment of experimental model for leukemia to develop novel molecular therapy

• Project/Area Number: 20790669
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Hematology
• Research Institution: The University of Tokyo
• Principal Investigator: GOYAMA Susumu The University of Tokyo, 医学部・附属病院, 助教 (80431849)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2009: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2008: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 白血病 / モデルマウス / 新規治療法 / Evi-1 / 難治性白血病 / マウス白血病モデル / Pten / Akt / mTorシグナル伝達経路 / 分子標的療法 / 造血幹細胞 / 白血病幹細胞 / MLL / Pbxl / ヒストンメチル化酵素

Research Abstract

Aberrant expression of Evi-1 has been shown as a poor-prognosis marker for acute myeloid leukemia (AML). In this study, we developed a colony replating assay to replicate Evi-1-related leukemia. Using this assay, we found several molecular mechanisms underlying Evi-1-mediated leukemogenesis as follows : (1) Evi-1 is upregulated by MLL oncoproteins. (2) Evi-1 activates Pbx1 and Akt/mTor pathway. (3) Evi-1 interacts with histone methyltransferases and polycomb complexes. Furthermore, we showed these factors are important for leukemogenic activities of Evi-1. These results provide a foundation to develop novel therapeutic strategies for AML.

Research Products

• [Journal Article] EVI-1 interacts with histone methyltransferases SUV39H1 and G9a for transcriptional repression and bone marrow immortalization. (2010)
  • Author(s): 合山進, 仁田英理子, 吉野哲也, 賀古真一, 渡辺-大河内直子, 島辺宗健, 今井陽一, 高橋孝喜, 黒川峰夫
  • Journal Title: Leukemia 24(1) Pages: 81-88
  • Peer Reviewed
• [Journal Article] 正常および白血病幹細胞におけるEvi-1の機能 (2010)
  • Author(s): 合山進、黒川峰夫
  • Journal Title: Annual review血液 Pages: 22-28
• [Journal Article] EVI-1 interacts with histone methyltransferases SUV39H1 and G9a for transcriptional repression and bone marrow immortalization (2010)
  • Author(s): Goyama S, Nitta E, Yoshino T, Kako S, Watanabe-Okochi N, Shimabe M, Imai Y, Takahashi K, Kurokawa M.
  • Journal Title: Leukemia 24(1) Pages: 81-88
  • Peer Reviewed
• [Journal Article] 正常および白血病幹細胞におけるEvi-1の機能 (2010)
  • Author(s): 合山進、黒川峰夫
  • Journal Title: Annual Review 血液 Pages: 22-28
• [Journal Article] Pbx1 is a downstream target of Evi-1 in hematopoietic stem/progenitors and leukemic cells. (2009)
  • Author(s): 島辺宗健, 合山進, 渡辺-大河内直子, 吉見昭英, 市川幹, 今井陽一, 黒川峰夫
  • Journal Title: Oncogene 28(49) Pages: 4364-4374
  • Peer Reviewed
• [Journal Article] Pathogenetic significance of ecotropic viral integration site-1 in hematological malignancies. (2009)
  • Author(s): 合山進, 黒川峰夫
  • Journal Title: Cancer Science 100(6) Pages: 990-995
  • NAID: 10025146207
  • Peer Reviewed
• [Journal Article] Evi-1による造血幹細胞制御と白血病発症機構 (2009)
  • Author(s): 合山進
  • Journal Title: Trends in Hematological Malignancies 1(2) Pages: 70-73
• [Journal Article] Evi-1による造血幹細胞制御と白血病発症 (2009)
  • Author(s): 合山進、黒川峰夫
  • Journal Title: 血液・腫瘍科 58(3) Pages: 354-360
  • NAID: 40019064494
• [Journal Article] Pathogenetic significance of ecotropic viral integration site-1 in hematological malignancies (2009)
  • Author(s): Goyama S, Kurokawa M.
  • Journal Title: Cancer Science 100(6) Pages: 990-995
  • NAID: 10025146207
  • Peer Reviewed
• [Journal Article] Pbx1 is a downstream target of Evi-1 in hematopoietic stem/progenitors and leukemic cells (2009)
  • Author(s): Shimabe M, Goyama S, Watanabe-Okochi N, Yoshimi A, Ichikawa M, Imai Y, Kurokawa M.
  • Journal Title: Oncogene 28(49) Pages: 4364-4374
  • Peer Reviewed
• [Journal Article] Evi-1 is a critical regulator for hematopoietic stem cells and transformed leukemic cells. (2008)
  • Author(s): 合山進, 山本豪, 島辺宗健, 佐藤智彦, 市川幹, 小川誠司, 千葉滋, 黒川峰夫
  • Journal Title: Cell Stem Cell 3(2) Pages: 207-220
  • NAID: 40019064494
  • Peer Reviewed
• [Journal Article] 転写因子と血液疾患 (2008)
  • Author(s): 合山進、黒川峰夫
  • Journal Title: BioClinica 23(12) Pages: 19-25
• [Journal Article] Evi-1 is a critical regulator for hematopoietic stem cells and transformed leukemic cells (2008)
  • Author(s): Goyama S, Yamamoto G, Shimabe M, Sato T, Ichikawa M, Ogawa S, Chiba S, Kurokawa M.
  • Journal Title: Cell Stem. Cell 3(2) Pages: 207-220
  • NAID: 40019064494
  • Peer Reviewed
• [Presentation] EVI1 Represses PTEN Transcription and Activates AKT/mTOR Through Interaction with Polycomb Repressor complexes (2009)
  • Author(s): 吉見昭秀, 渡辺-大河内直子, 合山進, 南谷泰仁, 仁田英里子, 荒井俊也, 佐藤智彦, 島辺宗健, 中川正宏, 今井陽一, 北村俊雄, 黒川峰夫
  • Organizer: 第71回日本血液学会総会
  • Place of Presentation: 京都
  • Year and Date: 2009-10-24
• [Presentation] EVI1はポリコーム群を介してPTENの転写抑制しAKT/mTORシグナルを活性化する (2009)
  • Author(s): 吉見昭秀, 渡辺-大河内直子, 合山進, 南谷泰仁, 仁田英里子, 荒井俊也, 佐藤智彦, 島辺宗健, 中川正宏, 今井陽一, 北村俊雄, 黒川峰夫
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-03
• [Presentation] 難治性白血病遺伝子Evi-1の分子生物的機能解析 (2009)
  • Author(s): 合山進、佐藤智彦、荒井俊也、島辺宗健、黒川峰夫
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2009-10-01
• [Presentation] Evi-1による造血幹細胞制御と白血病発症機構 (2009)
  • Author(s): 合山進
  • Organizer: 第5回麒麟塾
  • Place of Presentation: 東京
  • Year and Date: 2009-07-18
• [Presentation] Evi-1による造血幹細胞制御と白血病発症機構 (2009)
  • Author(s): 合山進
  • Organizer: 第5回麟麟塾
  • Place of Presentation: 東京
  • Year and Date: 2009-07-18
• [Presentation] Evi-1による造血幹細胞制御と白血病発症機構 (2009)
  • Author(s): 合山進
  • Organizer: 第7回先端血液学セミナー
  • Place of Presentation: 東京
  • Year and Date: 2009-06-13
• [Presentation] Function of Evi-1 as a leukemia-related transcription factor (2009)
  • Author(s): 合山進, 島辺宗健, 黒川峰夫
  • Organizer: USA-Japan Cooperative Cancer Workshop
  • Place of Presentation: Hawaii, U.S.A.
• [Presentation] Evi-1 Is a Direct Target of MLL Oncoproteins in Hematopoietic Stem Cells (2008)
  • Author(s): Arai S, Goyama S, Shimabe M, Ichikawa M, Imai Y, Takahashi T, Hangaishi A, Kurokawa M.
  • Organizer: 50th American Society of Hematology Annnual Meeting
  • Place of Presentation: San Francisco, U.S.A.
  • Year and Date: 2008-12-09
• [Presentation] Evi-1 Interacts with Histone Methyltransferases for Transcription Repression and Bone. Marrow Transformation (2008)
  • Author(s): Goyama S, Nitta E, Shimabe M, Yoshino T, Kako S, Ichikawa M, Imai Y, Takahashi T, Hangaishi A, Kurokawa M
  • Organizer: 50th American Society of Hematology Annnual Meeting
  • Place of Presentation: San Francisco, U.S.A.
  • Year and Date: 2008-12-08
• [Presentation] Pbx-1 Is a Direct Target of Evi-1 in Hematopoietic Stem/Progenitors and Leukemic Cells (2008)
  • Author(s): Shimabe M, Goyama S, Ichikawa M, Imai Y, Takahashi T, Hangaishi A, Kurokawa M.
  • Organizer: 50th American Society of Hematology Annnual Meeting
  • Place of Presentation: San Francisco, U.S.A.
  • Year and Date: 2008-12-07
• [Presentation] Regulation of hematopoietic stem cell activity and leukemogenesis by AML1 (2008)
  • Author(s): 西本菜穂子、市川幹、中川正弘、合山進、高橋強志、今井陽一、黒川峰夫
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-28
• [Presentation] Evi-1 up-regulates transcription of the PBX-1 gene in hematopoietic cells. (2008)
  • Author(s): 島辺宗健、合山進、市川幹、今井陽一、高橋強志、半下石明、黒川峰夫
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-28
• [Presentation] Evi-1 is up-regulated by MLL oncoproteins selectively in hematopoietic cells. (2008)
  • Author(s): 荒井俊也、合山進、島辺宗健、市川幹、今井陽一、高橋強志、半下石明、黒川峰夫
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-28
• [Presentation] Functional and physical interaction between oncogenic transcriptional factor Evi-1 and histone methyltransferases. (2008)
  • Author(s): 合山進、仁田英理子、島辺宗健、市川幹、今井陽一、高橋強志、半下石明、黒川峰夫
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-28
• [Presentation] 白血病標的遺伝子Evi-1によるヒストンメチル化修飾を介した転写制御機構 (2008)
  • Author(s): 合山進、仁田英理子、島辺宗健、市川幹、今井陽一、高橋強志、半下石明、黒川峰夫
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-28
• [Presentation] 白血病標的遺伝子Evi-1によるPBX-1の発現制御機構 (2008)
  • Author(s): 島辺宗健、合山進、市川幹、今井陽一、高橋強志、半下石明、黒川峰夫
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-28
• [Presentation] MLL融合遺伝子によるEvi-1の発現制御機構 (2008)
  • Author(s): 荒井俊也、合山進、島辺宗健、市川幹、今井陽一、高橋強志、半下石明、黒川峰夫
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-28
• [Presentation] 白血病標的遺伝子Evi-1によるヒストンメチル化修飾を介した転写制御機構 (2008)
  • Author(s): 合山進、仁田英里子、島辺宗健、吉野哲也、市川幹、今井陽一、高橋強志、黒川峰夫
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都
  • Year and Date: 2008-10-11
• [Presentation] 白血病標的遺伝子Evi-1によるPBX-1の発現制御機構 (2008)
  • Author(s): 島辺宗健、合山進、市川幹、今井陽一、高橋強志、半下石明、黒川峰夫
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都
  • Year and Date: 2008-10-11
• [Presentation] MLL融合遺伝子によるEvi-1の発現制御機構 (2008)
  • Author(s): 荒井俊也、合山進、島辺宗健、市川幹、今井陽一、高橋強志、半下石明、黒川峰夫
  • Organizer: 第70回日本血液学会総会
  • Place of Presentation: 京都
  • Year and Date: 2008-10-11
• [Presentation] Evi-1 Interacts with Histone Methyltransferases for Transcription Repression and Bone Marrow Transformation. (2008)
  • Author(s): 合山進, 仁田英理子, 島辺宗健, 吉野哲也, 賀古真一, 市川幹, 今井陽一, 高橋強志, 半下石明, 黒川峰夫
  • Organizer: 50th American Society of Hematology Annnual Meeting.
  • Place of Presentation: San Francisco, U.S.A.
• [Presentation] Evi-1 Is a Direct Target of MLL Oncoproteins in Hematopoietic Stem Cells. (2008)
  • Author(s): 荒井俊也, 合山進, 島辺宗健, 市川幹, 今井陽一, 高橋強志, 半下石明, 黒川峰夫
  • Organizer: 50th American Society of Hematology Annnual Meeting.
  • Place of Presentation: San Francisco, U.S.A.
• [Presentation] Pbx-1 Is a Direct Target of Evi-1 in Hematopoietic Stem/Progenitors and Leukemic Cells. (2008)
  • Author(s): 島辺宗健, 合山進, 市川幹, 今井陽一, 高橋強志, 半下石明, 黒川峰夫
  • Organizer: 50th American Society of Hematology Annnual Meeting.
  • Place of Presentation: Francisco, U.S.A.
• [Presentation] Evi-1による胎生期造血の制御機構 (2008)
  • Author(s): 佐藤智彦, 合山進, 黒川峰夫
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会大会合同大会
  • Place of Presentation: 神戸
• [Presentation] Evi-1によるヒストンメチル化修飾異常を介した白血病発症機構. (2008)
  • Author(s): 合山進、黒川峰夫
  • Organizer: 第12回がん分子標的治療研究会学術総会
  • Place of Presentation: 東京