Development of new treatment strategy targeting mitotic kinases in hematological malignancies

2010 Fiscal Year Final Research Report

• Project/Area Number: 20591131
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: Kochi University
• Principal Investigator: IKEZOE Takayuki Kochi University, 教育研究部・医療学系, 講師 (80294833)
• Project Period (FY): 2008 – 2010
• Keywords: 分裂期キナーゼ / 造血器悪性腫瘍

Research Abstract

Polo-like kinase1 (PLK1) belongs to the family of serine/threonine kinases and plays an important role in centrosome maturation, bipolar spindle formation, and cytokinesis during mitosis. We found in this study that PLK1 was aberrantly highly expressed in freshly isolated leukemia cells from individuals with acute myelogenous leukemia (AML, n=50) and acute lymphoblastic leukemia (ALL, n=15) compared to bone marrow mononuclear cells from healthy volunteers (n=13) (AML, p=0.016; ALL, p=0.008), as measured by real-time RT-PCR. Down-regulation of PLK1 by a small interfering RNA (siRNA) in NB4 AML cells inhibited their proliferation. GW843682X is a novel selective PLK1 inhibitor. The compound induced growth inhibition, caused accumulation of cells in the G2/M phase of the cell cycle and mediated apoptosis of human leukemia cells. Taken together, targeting PLK1 may be a promising treatment strategy for individuals with leukemia.

Research Products

• [Journal Article] AZ960, a novel Jak2 inhibitor induces growth arrest and apoptosis in adult T-cell leukemia cells. (2010)
  • Author(s): Yang J, Ikezoe T, Nishioka C, Furihata M, Yokoyama A.
  • Journal Title: Mol Cancer Ther. 12 Pages: 3386-3395
  • Peer Reviewed
• [Journal Article] cells to multi-targeted tyrosine kinase inhibitor induces activations of AKT, ERK and STAT5 signaling via epigenetic silencing of the PTEN gene. (2010)
  • Author(s): Nishioka C, Ikezoe T, Yang J, Yokoyama A.
  • Journal Title: Leukemia. 24 Pages: 1631-1640
  • Peer Reviewed
• [Journal Article] Kinase inhibitor-mediated apoptosis in acute myelogenous leukemia cells. (2010)
  • Author(s): Ikezoe T, Yang J, Nishioka C, Yokoyama A.
  • Journal Title: Int J Hematol. 91 Pages: 69-77
  • Peer Reviewed
• [Journal Article] mTORC1 by RAD001 (everolimus) potentiates the effects of 1,25-dihydroxyvitamin D(3) to induce growth arrest and differentiation of AML cells in vitro and in vivo. (2010)
  • Author(s): Yang J, Ikezoe T, Nishioka C, Ni L, Koeffler HP, Yokoyama A.
  • Journal Title: Exp Hematol. 38 Pages: 666-676
  • Peer Reviewed
• [Journal Article] treatment of imatinib-resistant hypereosinophilic syndrome with nilotinib. (2010)
  • Author(s): Ikezoe T, Togitani K, Tasaka T, Nishioka C, Yokoyama A.
  • Journal Title: Leuk Res. 34 Pages: e200-201
  • Peer Reviewed
• [Journal Article] induces apoptosis of acute myelogenous leukemia cells via inhibition of eukaryotic initiation factor 4E-binding protein 1 and down-regulation of Mcl-1. (2010)
  • Author(s): Nishioka C, Ikezoe T, Yang J, yokoyama A.
  • Journal Title: Apoptosis. 15 Pages: 795-804
  • Peer Reviewed
• [Journal Article] in non-Hodgkin lymphoma. (2009)
  • Author(s): Ikezoe T, Takeuchi T, Yang J, Adachi Y, Nishioka C, Furihata M, Koeffler HP, Yokoyama A.
  • Journal Title: Lab Invest. 89 Pages: 1364-1373
  • Peer Reviewed
• [Journal Article] inhibitor stimulates expression of IL-6 and activates JAK2/STAT5 signaling in acute myelogenous leukemia cells. (2009)
  • Author(s): Nishioka C, Ikezoe T, Yang J, Yokoyama A.
  • Journal Title: Leukemia. 23 Pages: 2304-2308
  • Peer Reviewed
• [Journal Article] receptor tyrosine kinase inhibitor, induces monocytic differentiation of acute myelogenous leukemia cells that is enhanced by 1,25-dihydroxyvitamin D(3). (2009)
  • Author(s): Nishioka C, Ikezoe T, Yang J, Yokoyama A.
  • Journal Title: Leukemia. 23 Pages: 2171-2173
  • Peer Reviewed
• [Journal Article] signaling enhances the ability of cytarabine to induce growth arrest and apoptosis of acute myelogenous leukemia cells. (2009)
  • Author(s): Nishioka C, Ikezoe T, Yang J, Yokoyama A.
  • Journal Title: Apoptosis 14 Pages: 1108-1120
  • Peer Reviewed
• [Journal Article] mammalian target of rapamycin signaling potentiates the effects of all-trans retinoic acid to induce growth arrest and differentiation of human acute myelogenous leukemia cells. (2009)
  • Author(s): Nishioka C, Ikezoe T, Yang J, Gery S, Koeffler HP, Yokoyama A.
  • Journal Title: Int J Cancer. 125 Pages: 1710-1720
• [Journal Article] Blockade of MEK signaling potentiates 5-Aza-2'-deoxycytidine-induced apoptosis and upregulation of leukemia cells. (2009)
  • Author(s): Nishioka C, Ikezoe T, Yang J, Komatsu N, Koeffler HP, Yokoyama A.
  • Journal Title: Int J Cancer. 125 Pages: 1168-1176
  • Peer Reviewed
• [Journal Article] targeting polo-like kinase 1 in hematological malignancies. (2009)
  • Author(s): Ikezoe T, Yang J, Nishioka C, Takezaki Y, Tasaka T, Togitani K, Koeffler HP, Yokoyama A.
  • Journal Title: Leukemia. 23 Pages: 1564-1576
  • Peer Reviewed
• [Presentation] CD34+/CD38- Leukemia Stem Cells Aberrantly Express CD82 Adhesion Molecule. 52nd ASH Annual Meeting and Exp (2010)
  • Author(s): Takayuki Ikezoe,Chie Nishioka, Jing Yang, Satoshi Serada, Tetsuji Naka, Akihito Yokoyama, Keiko Udaka.
  • Place of Presentation: Orange County Convention Center, Orlando, FL
  • Year and Date: 20101204-20101207
• [Presentation] Recombinant Human Soluble Thrombomodulin Enhances the Anti-Fibrinolytic and Ant Effects of All-Trans Retinoic Acute Promyelocytic Leukemia Cells. 52nd ASH Annual Meeting and Exp (2010)
  • Author(s): Takayuki Ikezoe, Jing Yang, Chie Nishioka, Mayuka Isaka, Naomi Iwabu, Mizu Sakai, Ayuko Taniguchi, Kazuto Togitani, Goichi Honda, Akihito Yokoyama.
  • Place of Presentation: Orange County Convention Center, Orlando, FL
  • Year and Date: 20101204-20101207
• [Presentation] P53 is critical for the Aurora B kinase inhibitor-mediated apoptosis in acute myelogenous leukemia cells. AACR 101st Annual Meeting 2010 (2010)
  • Author(s): Takayuki Ikezoe, Jing Yang, Chie Nishioka, Akihito Yokoyama.
  • Place of Presentation: Washington, DC
  • Year and Date: 20100417-20100421
• [Presentation] An oncogenic role for CCAAT/enbancer binding protein beta in non-small cell lung cancer. AACR 101st Annual Meeting 2010 (2010)
  • Author(s): Nils H.Thoennissen, Gabriela B.Iwanski, Jianfei Ji,Takayuki Ikezoe, Kunik Lee, Yoshihiro Adachi,Tamotsu Takeuchi, Mutsuo Furihata, Dorothy J.Park, Adrian F.Gombart, H.P.Koffler.
  • Place of Presentation: Washington, DC
  • Year and Date: 20100417-20100421
• [Presentation] Inhibition of STAT5 by IL-1β of the Inhibitor of Janus kinases Stimulates Dormant Humon Leukemia Stem Cells and Sensitizes Them to Anti-Leukemia Agents. 51ST ASH ANNUAL MEETING AND EXPOSITION (2009)
  • Author(s): Takayuki Ikezoe, Yang Jing, Chie Nisioka, Sinsuke Kojima, Asako Takeuchi, Akihito Yokoyama.
  • Place of Presentation: NEW ORLEANS
  • Year and Date: 20091205-20091208
• [Presentation] Development of a Novel Treatment Strategy Targeting JAK2 in Acute myelogenous Leukemia. 51ST ASH ANNUAL MEETING AND EXPOSITION (2009)
  • Author(s): Sinsuke Kojima, Takayuki Ikezoe, Mutsuo Furihata, Jing Yang, Chie Nisioka, Asako Takeuchi, Mayuka Isaka, H.Phillip Koeffler, Akihito Yokoyama.
  • Place of Presentation: NEW ORLEANS
  • Year and Date: 20091205-20091208