Role of Notch in the pathophysiology of leukemia stem cells and drug sensitivity tests for Notch inhibitors

• Project/Area Number: 20590557
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: TOHDA Shuji Tokyo Medical and Dental University, 大学院・医歯学総合研究科, 准教授 (80251510)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2008: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 臨床血液学 / 白血病 / 幹細胞 / Notch / 分子標的治療 / ガンマセクレターゼ / 白血病幹細胞 / Notchリガンド

Research Abstract

In order to treat leukemia effectively, we have to understand the pathophysiology of leukemia stem cells. Notch signaling is important for the regulation of self-renewal of leukemia stem cells. We found the molecular mechanism how the Notch ligand stimulation activates the Notch signaling and how it leads to cell growth. Moreover, we found that gamma-secretase inhibitors, which inhibit Notch signaling, suppress the growth of leukemia cells. We developed the methods to predict its effects.

Research Products

• [Journal Article] Effects of Combination of Notch Inhibitor plus Hedgehog Inhibitor or Wnt Inhibitor on Growth of Leukemia Cells. (2011)
  • Author(s): Okuhashi Y, Itoh M, Nara N, Tohda S
  • Journal Title: Anticancer Res. 31 Pages: 893-896
• [Journal Article] Promotionof the Self-renewal Capacity of Human Leukemia Cells by Sonic Hedgehog Protein. (2011)
  • Author(s): Kawaguchi-Ihara N, Okuhashi Y, Itoh M, Murohashi I, Nara N, Tohda S
  • Journal Title: Anticancer Res. 31 Pages: 781-784
• [Journal Article] Effects of gamma-secretase inhibitors on the growth of leukemia cells. (2010)
  • Author(s): Okuhashi Y, Nara N, Tohda S
  • Journal Title: Anticancer Res. 30 Pages: 495-498
• [Journal Article] Amplification of IGH/CCND1 fusion gene in a primary plasma cell leukemia case. (2010)
  • Author(s): Ishigaki T, Sasaki K, Watanabe K, Nakamura N, Toyota S, Kobayashi H, Tohda S
  • Journal Title: Cancer Genet Cytogenet. 201 Pages: 62-65
• [Journal Article] Gamma-secretase inhibitors induce erythroid differentiation in erythroid leukemia cell lines. (2010)
  • Author(s): Okuhashi Y, Itoh M, Arai A, Nara N, Tohda S
  • Journal Title: Anticancer Res. 30 Pages: 4071-4074
• [Journal Article] 白血病の分子標的治療のケミカルバイオロジー (2010)
  • Author(s): 東田修二
  • Journal Title: 臨床化学 39 Pages: 234-237
  • NAID: 10025632530
• [Journal Article] Effects of gamma-secretase inhibitors on the growth of leukemia cells (2010)
  • Author(s): Okuhashi Y, Nara N, Tohda S
  • Journal Title: Anticancer Research Volume: 30 Pages: 495-498
  • Peer Reviewed
• [Journal Article] Amplification of IGH/CCND1 fusion gene in a primary plasma cell leukemia-case (2010)
  • Author(s): Ishigaki T, Sasaki K, Kobayashi H, Tohda S
  • Journal Title: Cancer Genetics and Cytogenetics Volume: 201 Pages: 62-65
  • Peer Reviewed
• [Journal Article] Gamma-secretase inhibitors induce erythroid differentiation in erythroid leukemia cell lines (2010)
  • Author(s): Okuhashi Y, Itoh M, Arai A, Nara N, Tohda S
  • Journal Title: Anticancer Research Volume: 30 Pages: 4071-4074
  • Peer Reviewed
• [Journal Article] Cyclopamine and quercetin suppress the growth of leukemia and lymphoma cells. (2009)
  • Author(s): Kawahara T, Kawaguchi-Ihara N, Okuhashi Y, Itoh M, Nara N, Tohda S
  • Journal Title: Anticancer Res. 29 Pages: 4629-4632
• [Journal Article] Transition of cleaved Notch1 and gene expression changes in myeloblastic leukemia cells stimulated with notch ligands. (2009)
  • Author(s): Fu L, Katsube K, Tohda S
  • Journal Title: Anticancer Res. 29 Pages: 3967-3970
• [Journal Article] NF-kappaB activation induced by Notch ligandstimulation in acute myeloid leukemia cells. (2009)
  • Author(s): Itoh M, Fu L, Tohda S
  • Journal Title: Oncol Rep. 22 Pages: 631-634
• [Journal Article] 白血病の病態におけるNotchの機能解析 (2009)
  • Author(s): 東田修二
  • Journal Title: 臨床病理 57 Pages: 351-356
  • NAID: 10025224703
• [Journal Article] Transition of cleaved Notch1 and gene expression changes in myeloblastic leukemia cells stimulated with notch ligands (2009)
  • Author(s): Fu L, Katsube K, Tohda S
  • Journal Title: Anticancer Research 29 Pages: 3967-3970
  • Peer Reviewed
• [Journal Article] NF-kappaB activation induced by Notch ligand stimulation in acute myeloid leukemia cells (2009)
  • Author(s): Itoh M, Fu L, Tohda S
  • Journal Title: Oncology Reports 22 Pages: 631-634
  • Peer Reviewed
• [Journal Article] Cyclopamine and quercetin suppress the growth of leukemia and lymphoma cells (2009)
  • Author(s): Kawahara T, Kawaguchi-Ihara N, Okuhashi Y, Itoh M, Nara N, Tohda S
  • Journal Title: Anticancer Research 29 Pages: 4629-4632
  • Peer Reviewed
• [Journal Article] Promotion of the self-renewal capacity of human acute leukemia cells by Wnt3A. (2008)
  • Author(s): Kawaguchi-Ihara N, Murohashi I, Nara N, Tohda S
  • Journal Title: Anticancer Res. 28 Pages: 2701-2704
• [Journal Article] Expression and function of the Delta-1/Notch-2/Hes-1 pathway during experimental acute kidney injury. (2008)
  • Author(s): Kobayashi T, Terada Y, Kuwana H, Tanaka H, Okado T, Kuwahara M, Tohda S, Sakano S, Sasaki S.
  • Journal Title: Kidney Int 73 Pages: 1240-1250
• [Journal Article] Negative feedback regulation of colitogenic CD4+ T cells by increased granulopoiesis. (2008)
  • Author(s): Nemoto Y, Kanai T, Tohda S, Totsuka T, Okamoto R, Tsuchiya K, Nakamura T, Sakamoto N, Fukuda T, Miura O, Yagita H, Watanabe M.
  • Journal Title: Inflamm Bowel Dis 14 Pages: 1491-1503
• [Journal Article] Promotion of the self-renewal capacity of human acute leukemia cells by Wnt3A (2008)
  • Author(s): Kawaguchi-Ihara N, Murohashi I, Nara N, Tohda S
  • Journal Title: Anticancer Research 28 Pages: 2701-2704
  • Peer Reviewed
• [Journal Article] Expression and function of the Delta-1/Notch-2/Hes-1 pathway during experimental acute kidney injury (2008)
  • Author(s): Kobayashi T, Terada Y, Kuwana H, Tanaka H, Okado T, KUwahara M, Tohda S, Sakano S, Sasaki S
  • Journal Title: Kidney International 73 Pages: 1240-1250
  • Peer Reviewed
• [Journal Article] Negative feedback regulation of colitogenie CD4+T cells byincreased granulopoiesis (2008)
  • Author(s): Nemoto Y, Kanai T, Tohda s, Totsuka T, Okamoto R, Tsuchiya K, Nakamura T, Sakamoto N, Fukuda T, Miura O, Yagita H, Watanabe M
  • Journal Title: Inflammatory Bowel Diseases 14 Pages: 1491-1503
  • Peer Reviewed
• [Presentation] 白血病細胞の増殖におけるNotchシグナルとWnt, Hedgehogシグナルとの相互作用 (2010)
  • Author(s): 奥橋佑基, 石垣知寛, 伊藤真以, 東田修二
  • Organizer: 第57回日本臨床検査医学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2010-09-10
• [Presentation] 白血病細胞の増殖におけるNotchシグナルとWnt, Hedgehogシグナルとの相互作用 (2010)
  • Author(s): 奥橋佑基, 石垣知寛, 伊藤真以, 東田修二
  • Organizer: 第57回日本臨床検査医学会学術集会
  • Place of Presentation: 京王プラザホテル(東京都)
  • Year and Date: 2010-09-10
• [Presentation] 白血病の分子標的治療のケミカルバイオロジー (2009)
  • Author(s): 東田修二
  • Organizer: 第49回日本臨床化学会学術集会ワークショップ
  • Place of Presentation: 長崎
  • Year and Date: 2009-09-18
• [Presentation] 白血病の分子標的治療のケミカルバイオロジー (2009)
  • Author(s): 東田修二
  • Organizer: 第49回日本臨床化学会学術集会
  • Place of Presentation: 長崎大学医学部
  • Year and Date: 2009-09-18
• [Presentation] Notchシグナル阻害剤による赤白血病細胞の赤芽球分化誘導効果 (2009)
  • Author(s): 奥橋佑基、河原達雄、井原寛子、星百合子、東田修二
  • Organizer: 第56回日本臨床検査医学会総会
  • Place of Presentation: 札幌
  • Year and Date: 2009-08-28
• [Presentation] 日本臨床検査医学会学会賞生命科学賞受賞、受賞講演.白血病の病態におけるNotchの機能解析 (2008)
  • Author(s): 東田修二
  • Organizer: 第55回日本臨床検査医学会総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-11-28
• [Presentation] 白血病の病態におけるNotchの機能解析 (2008)
  • Author(s): 東田修二
  • Organizer: 第55回日本臨床検査医学会総会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2008-11-28
• [Book] 急性白血病、血友病など17項目(福井次矢、奈良信雄 編)(内科診断学第2版) (2008)
  • Author(s): 東田修二
  • Publisher: 医学書院
• [Book] 可溶性IL-2レセプター、顆粒球コロニー刺激因子など15項目(櫻林郁之介、熊坂一成監修)(最新臨床検査項目辞典) (2008)
  • Author(s): 東田修二
  • Publisher: 医歯薬出版
• [Remarks] ホームページ等
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