Development of novel therapeutic strategy for targeting transcription factors expressed in cancer stem cells

• Project/Area Number: 18390282
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: University of Yamanashi
• Principal Investigator: KOMATSU Norio University of Yamanashi, 大学院・医学工学総合研究部, 教授 (50186798)
• Co-Investigator(Kenkyū-buntansha): KIRITO Keita 山梨大学, 医学部・附属病院, 准教授 (90306150) ; KUNITAMA Masae 山梨大学, 医学部・附属病院, 助教 (60397297) ; NAGASHIMA Takahiro 山梨大学, 医学部・附属病院, 助教 (10343443) ; MITSUMORI Toru 山梨大学, 医学部・附属病院, 助教 (80377514) ; SAKOE Kumi 山梨大学, 医学部・附属病院, 助教 (10398505)
• Project Period (FY): 2006 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,340,000 (Direct Cost: ¥15,400,000、Indirect Cost: ¥2,940,000); Fiscal Year 2008: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2007: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000); Fiscal Year 2006: ¥5,600,000 (Direct Cost: ¥5,600,000)
• Keywords: 血液内科学 / 白血病 / 抗癌薬 / 薬剤耐性 / 寿命関連遺伝子 / アポトーシス / 急性前骨髄球性白血病 / FOXO3A / オールトランスレチノイン酸 / 分子標的治療 / protein phosphatase 2A / FTY720 / HIF-1 / 多発性骨髄腫 / survivin / IGF-1

Research Abstract

癌患者に抗癌剤を投与すると経過中にその効果が減弱することがある。この薬剤耐性にはさまざまな機序が関与しており、いかに耐性を克服するかが治療戦略を考える上で重要な鍵となる。我々は寿命に関連する転写因子であるFOXO3A に注目し、その分子を細胞の核内に強制的に発現させることで抗癌剤に耐性を獲得した細胞をも死滅させることを明らかにした。このことはFOXO3A を核内に発現できる薬剤こそが万能な抗癌剤となりうることを示唆している。

Research Products

• [Journal Article] Identification of erythropoietin-induced microRNAs in hematopoietic cells during erythroid differentiation (2008)
  • Author(s): Kosaka N, Sugiura K,Yamamoto Y, Yoshioka Y, Miyazaki H, Komatsu N, Ochiya T, Kato T.
  • Journal Title: Br J Haematol 142 Pages: 293-300
  • Peer Reviewed
• [Journal Article] Thrombopoietin (TPO) regulates HIF-1a levels through generation of mitochondrial reactive oxygen species (2008)
  • Author(s): Yoshida K, Kirito K, Yongzhen H,Ozawa K, Kaushansky K, Komatsu N.
  • Journal Title: Int J Hematol 88(1) Pages: 43-51
  • Peer Reviewed
• [Journal Article] Hemin reduces cellular sensitivity to imatinib and anthracyclins via Nrf2 (2008)
  • Author(s): Nagai T, Kikuchi S, Ohmine K, Miyoshi T, Nakamura M, Kondo T, Furuyama K, Komatsu N, Ozawa K.
  • Journal Title: J Cell Biochem 104(2) Pages: 680-691
  • Peer Reviewed
• [Journal Article] novel RUNX1 mutation in familial platelet disorder with propensity to develop myeloid malignancies (2008)
  • Author(s): Kirito K, Sakoe K, Shinoda D, Takiyama Y, Kaushansky K, Komatsu N.
  • Journal Title: Haematologica 93 Pages: 155-156
  • Peer Reviewed
• [Journal Article] Regulation of erythropoiesis and pathogenesis of anemia (2008)
  • Author(s): Komatsu N.
  • Journal Title: Nippon Rinsho 66 Pages: 420-422
  • NAID: 40015862583
• [Journal Article] Pure erythroid leukemia (M6b) (2008)
  • Author(s): Mitsumori T
  • Journal Title: Rinsho Ketsueki 49 Pages: 1-2
  • NAID: 10021256744
• [Journal Article] Identification of erythropoietin-induced microRNAs in hematopoietic cells during erythroid differentiation (2008)
  • Author(s): Kosaka N
  • Journal Title: Br J Haematol 142 Pages: 293-300
  • Peer Reviewed
• [Journal Article] Thrombopoietin (TPO) regulates HIF-la levels through generation of mitochondrial reactiv eoxygen species (2008)
  • Author(s): Yoshida K
  • Journal Title: Int J Hematol 88 Pages: 43-51
  • Peer Reviewed
• [Journal Article] Hemin reduces cellular sensitivity to imatinib and anthracyclins via Nrf2 (2008)
  • Author(s): Nagai T
  • Journal Title: J Cell Biochem 104 Pages: 680-691
  • Peer Reviewed
• [Journal Article] A novel RUNX1 mutation in familial platelet disorder with propensity to develop myeloid maligna (2008)
  • Author(s): Kirito K
  • Journal Title: Haematologica 93 Pages: 155-156
  • Peer Reviewed
• [Journal Article] Identification of erythropoietin-induced microRNAs in hematopoietic cells during erythroid differentiation. (2008)
  • Author(s): Kosaka N
  • Journal Title: Bri J Haematol (In press)
  • Peer Reviewed
• [Journal Article] Thrombopoietin(TPO)regulates HIF-1a levels through generation of mitochondrial reactive oxygen species. (2008)
  • Author(s): Yoshida K
  • Journal Title: Int J Hematol (In press)
  • Peer Reviewed
• [Journal Article] Hemin reduces cellular sensitivity to imatinib and anthracyclins via Nrf2. (2008)
  • Author(s): Nagai T
  • Journal Title: J Cell Biochem (In press)
  • Peer Reviewed
• [Journal Article] novel RUNX1 mutation in familial platelet disorder with propensity to develop myeloid malignancies. (2008)
  • Author(s): Kirito K
  • Journal Title: Haematologica 93 Pages: 155-156
  • Peer Reviewed
• [Journal Article] Regulation of erythropoiesis and pathogenesis of anemia. (2008)
  • Author(s): Komatsu N
  • Journal Title: Nippon Rinsho 66 Pages: 420-422
  • NAID: 40015862583
  • Peer Reviewed
• [Journal Article] Pure erythroid leukemia(M6b). (2008)
  • Author(s): Mitsumori T
  • Journal Title: Rinsho Ketsueki 49 Pages: 1-2
  • NAID: 10021256744
• [Journal Article] Activation of FKHRL1 plays an important role in protecting erythroid cells from erythropoietin deprivation-induced apoptosis in a human erythropoietin-dependent leukemia cell line (2007)
  • Author(s): Uchida M, Kirito K, Endo H, Ozawa K, Komatsu N.
  • Journal Title: UT-7/EPO. Int J Hematol 86(4) Pages: 315-24
  • Peer Reviewed
• [Journal Article] Cloning and characterization of a human BCR/ABL-positive cell line (2007)
  • Author(s): Miyoshi T, Nagai T, Kikuchi S, Ohmine K, Nakamura M, Hanafusa T, Komatsu N, Ozawa K.
  • Journal Title: K562/RR, resistant to the farnesyltransferase inhibition by tipifarnib. Exp Hematol 35(9) Pages: 1358-65
  • Peer Reviewed
• [Journal Article] Active FKHRL1 overcomes imatinib resistance in chronic myelogenous leukemia-derived cell lines via the production of tumor necrosis factor-related apoptosisinducing ligand (2007)
  • Author(s): Kikuchi S, Nagai T, Kunitama M, Kirito K, Ozawa K, Komatsu N.
  • Journal Title: Cancer Sci 98(12) Pages: 1949-58
  • Peer Reviewed
• [Journal Article] Erythropoietin for the treatment of chemotherapy-induced anemia (2007)
  • Author(s): Komatsu N.
  • Journal Title: Rinsho Ketsueki 48(10) Pages: 1435-41
  • NAID: 10019829495
• [Journal Article] Divergent cytotoxic effects of PKC412 in combination with conventional antileukemic agents in FLT3 mutation-positive versus -negative leukemia cell lines (2007)
  • Author(s): Furukawa Y, Vu HA, Akutsu M, Odgerel T, Izumi T, Tsunoda S, Matsuo Y, Kirito K, Sato Y, Mano H, Kano Y.
  • Journal Title: 21(5) Pages: 1005-14
  • Peer Reviewed
• [Journal Article] Activation of FKHRL1 plays an important role in protecting erythroid cells from erythropoietin deprivation-induced apoptosis in a human erythropoietin-dependent leukemia cell line, U-7/EPO. (2007)
  • Author(s): Uchida M
  • Journal Title: Int J Hematol 86 Pages: 315-324
  • Peer Reviewed
• [Journal Article] Cloning and characterization of a human BCR/ABL-positive cell line, K562/RR, resistant to the farnesyltransferase inhibition by tipifarnib. (2007)
  • Author(s): Miyoshi T
  • Journal Title: Exp Hematol 35 Pages: 1358-1365
  • Peer Reviewed
• [Journal Article] Active FKHRL1 overcomes imatinib resistance in chronic myelogenous leukemia-derived cell lines via the production of tumor necrosis factor-related apoptosis-inducing ligand. (2007)
  • Author(s): Kikuchi S
  • Journal Title: Cancer Sci 98 Pages: 1949-1958
  • Peer Reviewed
• [Journal Article] Multiple myeloma with grape cell-like changes in almost all myeloma cells. (2007)
  • Author(s): Mitsumori T
  • Journal Title: Rinsho Ketsueki 48 Pages: 1453-1453
• [Journal Article] Erythropoietin for the treatment of chemotherapy-induced anemia (2007)
  • Author(s): Komatsu N
  • Journal Title: Rinsho Ketsueki 48 Pages: 1435-1441
  • NAID: 10019829495
• [Journal Article] Divergent cytotoxic effects of PKC412 in combination with conventional antileukemic agents in FLT3 mutation-positive versus -mugative leukemia cell lines (2007)
  • Author(s): Furukawa Y.
  • Journal Title: Leukemia (In press)
• [Journal Article] RUNX1 suppression induces megakaryocytic differentiation of UT- 7/GM cells (2006)
  • Author(s): Nagai R, Matsuura E, Hoshika Y, Nakata E, Nagura H, Watanabe A, Komatsu N, Okada Y, Doi T.
  • Journal Title: Biochem Biophys Res Commun 345 Pages: 78-84
  • Peer Reviewed
• [Journal Article] K.Transcriptional regulation of megakaryopoiesis: thrombopoietin signaling and nuclear factors (2006)
  • Author(s): Kirito K, Kaushansky K.
  • Journal Title: Curr Opin Hematol 13(3) Pages: 151-156
  • Peer Reviewed
• [Journal Article] Pleocytosis after hemopoietic stem cell transplantation (2006)
  • Author(s): Nagashima T, Muroi K, Kawano-Yamamoto C, Miyoshi T, Tatara R, Meguro A, Fujiwara S, Obara Y, Oh I, Kikuchi S, Sato K, Matsuyama T, Toshima M, Ohmine K, Ozaki K, Takatoku M, Mori M, Nagai T,Ozawa K.
  • Journal Title: Leuk Lymphoma 47(8) Pages: 1613-1617
  • Peer Reviewed
• [Journal Article] Suppression of RUNX1 by siRNA in megakaryocytic UT-7/GM cells (2006)
  • Author(s): Okada Y, Nagai R, Matsuura E, Hoshika Y, Nakata E, Nagura H, Watanabe A, Komatsu N, Doi T.
  • Journal Title: Nucleic Acids Symposium Series 50 Pages: 261-262
  • Peer Reviewed
• [Journal Article] RUNX1 suppression induces megakaryocytic differentiation of UT-7/GM cells. (2006)
  • Author(s): Nagai R.
  • Journal Title: Biochem Biophys Res Commun 345 Pages: 78-84
• [Journal Article] Transcriptional regulation of megakaryopoiesis : thrombopoiet in signaling and nuclear factors. (2006)
  • Author(s): Kirito K.
  • Journal Title: Curr Opin Hematol 13・3 Pages: 151-156
• [Journal Article] Pleocytosis after hemopoietic stem cell transplantation. (2006)
  • Author(s): Nagashima T.
  • Journal Title: Leuk Lymphoma 47・8 Pages: 1613-1617
• [Journal Article] Suppression of RUNX1 by 視RNA in megakaryocytic UT-7/GM cells (2006)
  • Author(s): Okada Y.
  • Journal Title: Nucleic Acids Symposium Series 50 Pages: 261-262
• [Presentation] HIF-1 Prevents Hematopoietic Cells from Cell Damage by Overproduction of Mitochondrial ROS after Cytokine Stimulation through Induction of PDK-1 (2008)
  • Author(s): Keita Kirito, Kozue Yoshida, Yongzhen Hu, Qiao Qiao, Kumi Sakoe, and Norio Komatsu
  • Organizer: 第50回米国血液学会
  • Place of Presentation: San Francisco
  • Year and Date: 2008-12-07
• [Presentation] HIF-1 Prevents Hematopoietic Cells from Cell Damage by Overproduction of Mitochondrial ROS after Cytokine Stimulation through Induction of PDK-1. (2008)
  • Author(s): Keita K
  • Organizer: 第50回米国血液学会
  • Place of Presentation: San Francisco
  • Year and Date: 2008-12-07
• [Presentation] HIF-1 Supports the Survival of Multiple Myeloma Cells through the Induction of Survivin Gene (2007)
  • Author(s): Kirito K
  • Organizer: 第49回米国血液学会
  • Place of Presentation: Atlanta
  • Year and Date: 2007-12-09
• [Presentation] Expression of miR-188 and 362 Induced by Erythropoietin Stimulation in a Human Erythrocytic Leukemia Cell Line (2007)
  • Author(s): Sugiura K.
  • Organizer: 第49回米国血液学会
  • Place of Presentation: Atlanta
  • Year and Date: 2007-12-09
• [Presentation] Expression of miR-188 and 362 Induced byEry1hropoietin Stimulation in a Human Erythrocytic Ieukemia Cell Line. (2007)
  • Author(s): Sugiura K
  • Organizer: 第49回米国血液学会
  • Place of Presentation: Atlanta
  • Year and Date: 2007-12-09
• [Presentation] Regulation of miR-210 Generation in Response to Hypoxia in Erythrocytic Cells (2007)
  • Author(s): Kosaka N.
  • Organizer: 第49回米国血液学会
  • Place of Presentation: Atlanta
  • Year and Date: 2007-12-08
• [Presentation] Regulation of miR-210 Generation in Response to Hypoxia in Erythrocytic Cells. (2007)
  • Author(s): Kosaka N
  • Organizer: 第49回米国血液学会
  • Place of Presentation: Atlanta
  • Year and Date: 2007-12-08