Research & Development of molecular target therapy for leukemia and Its assessment System

2009 Fiscal Year Final Research Report

• Project/Area Number: 17016029
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Nagoya University
• Principal Investigator: NAOE Tomoki Nagoya University, 大学院・医学系研究科, 教授 (50217634)
• Project Period (FY): 2005 – 2009
• Keywords: 白血病 / シグナル伝達 / 幹細胞 / 分子標的治療 / キメラ転写因子

Research Abstract

For the development of more effective and secure target therapy for leukemia, we clarified that mutated FLT3 and KIT, and N-CoR/HDAC3/TBLR1 complex that is recruited by chimera transcription factor PML-RARA are ideal target molecules/complex for therapy. We developed FLT3 inhibitors, FI-700 and KW-2449, and KIT inhibitor, KI-328. For targeting N-CoR/HDAC3/TBLR1 complex we designed a decoy peptide. We also established a laboratory system which can evaluate p-FLT3 or p-STAT5 of leukemia cells using FACS and estimate pharmaco-dynamismly plasma bioassay system.

Research Products

• [Journal Article] BCR-ABL-independent and RAS / MAPK pathway-dependent form of imatinib resistance in Ph-positive acute lymphoblastic leukemia cell line with activation of EphB4 (2010)
  • Author(s): Suzuki M, Abe A, Imagama S, Nomura Y, Tanizaki R, Minami Y, Hayakawa F, Ito Y, Katsumi A, Yamamoto K, Emi N, Kiyoi H, Naoe T
  • Journal Title: Eur J Haematol 84 Pages: 229-38
  • Peer Reviewed
• [Journal Article] KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation (2009)
  • Author(s): Shiotsu Y, Kiyoi H, Ishikawa Y, Tanizaki R, Shimizu M, Umehara H, Ishii K, Mori Y, Ozeki K, Minami Y, Abe A, Maeda H, Akiyama T, Kanda Y, Sato Y, Akinaga S, Naoe T.
  • Journal Title: Blood. 114 Pages: 1607-17
  • Peer Reviewed
• [Journal Article] Comprehensive analysis of cooperative gene mutations between class I and class II in de novo acute myeloid leukemia (2009)
  • Author(s): Ishikawa Y, Kiyoi H, Tsujimura A, Miyawaki S, Miyazaki Y, Kuriyama K, Tomonaga M, Naoe T.
  • Journal Title: Eur J Haematol 83 Pages: 90-8
  • Peer Reviewed
• [Journal Article] GATA-1 and GATA-2 binding to 3' enhancer of WT1 gene is essential for its transcription in acute leukemia and solid tumor cell lines (2009)
  • Author(s): Furuhata A, Murakami M, Ito H, Gao S, Yoshida K, Sobue S, Kikuchi R, Iwasaki T, Takagi A, Kojima T, Suzuki M, Abe A, Naoe T, Murate T.
  • Journal Title: Leukemia. 23 Pages: 1270-7
  • Peer Reviewed
• [Journal Article] Retention but significant reduction of BCR-ABL transcript in hematopoietic stem cells in chronic myelogenous leukemia after imatinib therapy (2008)
  • Author(s): Abe A, Minami Y, Hayakawa F, Kitamura K, Nomura Y, Murata M, Katsumi A, Kiyoi H, Jamieson CH, Wang JY, Naoe T.
  • Journal Title: Int J Hematol. 88 Pages: 471-5
  • Peer Reviewed
• [Journal Article] BCR-ABL-transformed GMP as myeloid leukemic stem cells (2008)
  • Author(s): Minami Y, Stuart SA, Ikawa T, Jiang Y, Banno A, Hunton IC, Young DJ, Naoe T, Murre C, Jamieson CH, Wang JY.
  • Journal Title: Proc Natl Acad Sci U S A 105 Pages: 17967-72
  • Peer Reviewed
• [Journal Article] Prognostic implication and biological roles of RhoH in acute myeloid leukaemia (2008)
  • Author(s): Iwasaki T, Katsumi A, Kiyoi H, Tanizaki R, Ishikawa Y, Ozeki K, Kobayashi M, Abe A, Matsushita T, Watanabe T, Amano M, Kojima T, Kaibuchi K, Naoe T.
  • Journal Title: Eur J Haematol 81 Pages: 454-60
  • Peer Reviewed
• [Journal Article] Clinical significance of nuclear non-phosphorylated beta-catenin in acute myeloid leukaemia and myelodysplastic syndrome (2008)
  • Author(s): Xu J, Suzuki M, Niwa Y, Hiraga J, Nagasaka T, Ito M, Nakamura S, Tomita A, Abe A, Kiyoi H, Kinoshita T, Naoe T.
  • Journal Title: Br J Haematol. 140 Pages: 394-401
  • Peer Reviewed
• [Journal Article] FLT3 regulates beta-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells (2007)
  • Author(s): Kajiguchi T, Chung EJ, Lee S, Stine A, Kiyoi H, Naoe T, Levis MJ, Neckers L, Trepel JB.
  • Journal Title: Leukemia 21 Pages: 2476-84
  • Peer Reviewed
• [Journal Article] A novel FLT3 inhibitor FI-700 selectively suppresses the growth of leukemia cells with FLT3 mutations (2007)
  • Author(s): Kiyoi H, Shiotsu Y, Ozeki K, Yamaji S, Kosugi H, Umehara H, Shimizu M, Arai H, Ishii K, Akinaga S, Naoe T.
  • Journal Title: Clin Cancer Res. 13(15Pt1) Pages: 4575-82
  • Peer Reviewed
• [Journal Article] PML-retinoic acid receptor alpha inhibits PML IV enhancement of PU. 1-induced C/EBPepsilon expression in myeloid differentiation (2007)
  • Author(s): Yoshida H, Ichikawa H, Tagata Y, Katsumoto T, Ohnishi K, Akao Y, Naoe T, Pandolfi PP, Kitabayashi I.
  • Journal Title: Mol Cell Biol 27 Pages: 5819-34
  • Peer Reviewed
• [Journal Article] LRP16 is fused to RUNX1 in monocytic leukemia cell line with t(11;21)(q13;q22) (2007)
  • Author(s): Imagama S, Abe A, Suzuki M, Hayakawa F, Katsumi A, Emi N, Kiyoi H, Naoe T.
  • Journal Title: Eur J Haematol. 79 Pages: 25-31
  • Peer Reviewed
• [Journal Article] JAK3 mutations occur in acute megakaryoblastic leukemia both in Down syndrome children and non-Down syndrome adults (2007)
  • Author(s): Kiyoi H, Yamaji S, Kojima S, Naoe T.
  • Journal Title: Leukemia 21 Pages: 574-6
  • Peer Reviewed
• [Journal Article] Lyn is an important component of the signal transduction pathway specific to FLT3/ITD and can be a therapeutic target in the treatment of AML with FLT3/ITD (2007)
  • Author(s): Okamoto M, Hayakawa F, Miyata Y, Watamoto K, Emi N, Abe A, Kiyoi H, Towatari M, Naoe T.
  • Journal Title: Leukemia 21 Pages: 403-10
  • Peer Reviewed
• [Journal Article] Homing, proliferation and survival sites of human leukemia cells in vivo in immunodeficient mice (2007)
  • Author(s): Ninomiya M, Abe A, Katsumi A, Xu J, Ito M, Arai F, Suda T, Ito M, Kiyoi H, Kinoshita T, Naoe T.
  • Journal Title: Leukemia 21 Pages: 136-42
  • Peer Reviewed
• [Journal Article] Establishment of a stroma-dependent human acute myelomonocytic leukemia cell line, NAMO-2, with FLT3 tandem duplication (2006)
  • Author(s): Abe A, Kiyoi H, Ninomiya M, Yamazaki T, Murase T, Ozeki K, Suzuki M, Hayakawa F, Katsumi A, Emi N, Naoe T.
  • Journal Title: Int J Hematol 84 Pages: 328-36
  • Peer Reviewed
• [Journal Article] Biology, clinical relevance, and molecularly targeted therapy in acute leukemia with FLT3 mutation (2006)
  • Author(s): Kiyoi H, Naoe T.
  • Journal Title: Int J Hematol 83 Pages: 301-8
  • Peer Reviewed
• [Journal Article] Histone deacetylase 3 (HDAC3) is recruited to target promoters by PML-RARalpha as a component of the N-CoR co-repressor complex to repress transcription in vivo (2006)
  • Author(s): Atsumi A, Tomita A, Kiyoi H, Naoe T.
  • Journal Title: Biochem Biophys Res Commun. 345 Pages: 1471-80
  • Peer Reviewed
• [Journal Article] PTPN11, RAS and FLT3 mutations in childhood acute lymphoblastic leukemia (2006)
  • Author(s): Yamamoto T, Isomura M, Xu Y, Liang J, Yagasaki H, Kamachi Y, Kudo K, Kiyoi H, Naoe T, Kojma S.
  • Journal Title: Leuk Res. 30 Pages: 1085-9
  • Peer Reviewed
• [Journal Article] Mutations of N-RAS, FLT3 and p53 genes are not involved in the development of acute leukemia transformed from myeloproliferative diseases with JAK2 mutation (2006)
  • Author(s): Suzuki M, Abe A, Kiyoi H, Murata M, Ito Y, Shimada K, Morishita Y, Kinoshita T, Naoe T.
  • Journal Title: Leukemia 20 Pages: 1168-9
  • Peer Reviewed
• [Journal Article] Japan Adult Leukemia Study Group. High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group (2006)
  • Author(s): Yanada M, Takeuchi J, Sugiura I, Akiyama H, Usui N, Yagasaki F, Kobayashi T, Ueda Y, Takeuchi M, Miyawaki S, Maruta A, Emi N, Miyazaki Y, Ohtake S, Jinnai I, Matsuo K, Naoe T, Ohno R
  • Journal Title: J Clin Oncol. 24 Pages: 460-6
  • Peer Reviewed
• [Journal Article] BMI-1 is highly expressed in M0-subtype acute myeloid leukemia. (2005)
  • Author(s): Sawa M, Yamamoto K, Yokozawa T, Kiyoi H, Hishida A, Kajiguchi T, Seto M, Kohno A, Kitamura K, Itoh Y, Asou N, Hamajima N, Emi N, Naoe T.
  • Journal Title: Int J Hematol 82 Pages: 42-7
  • Peer Reviewed
• [Journal Article] Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia (2005)
  • Author(s): Suzuki T, Kiyoi H, Ozeki K, Tomita A, Yamaji S, Suzuki R, Kodera Y, Miyawaki S, Asou N, Kuriyama K, Yagasaki F, Shimazaki C, Akiyama H, Nishimura M, Motoji T, Shinagawa K, Takeshita A, Ueda R, Kinoshita T, Emi N, Naoe T.
  • Journal Title: Blood 106 Pages: 2854-61
  • Peer Reviewed
• [Journal Article] Efficacy of gemtuzumab ozogamicin on ATRA- and arsenic-resistant acute promyelocytic leukemia (APL) cells (2005)
  • Author(s): Takeshita A, Shinjo K, Naito K, Matsui H, Sahara N, Shigeno K, Horii T, Shirai N, Maekawa M, Ohnishi K, Naoe T, Ohno R.
  • Journal Title: Leukemia 19 Pages: 1306-11
  • Peer Reviewed
• [Journal Article] Irrespective of CD34 expression, lineage-committed cell fraction reconstitutes and re-establishes transformed Philadelphia chromosome-positive leukemia in NOD / SCID / IL-2Rgammac mice
  • Author(s): Tanizaki R, Naoe T., et al.
  • Journal Title: Cancer Sci. 2009(in Press)
  • Peer Reviewed
• [Presentation] MS4A1 (CD20) Gene Expression Is Down-Regulated by Recruiting the Histone Deacetylase Protein Complex to the Promoter in the CD20-Negative B-Lymphoma Cells After Treatment with Rituximab (2009)
  • Author(s): Sugimoto T, Naoe T, et al.
  • Organizer: The American Society of Hematology 51th Annual Meeting
  • Place of Presentation: New Orleans USA
  • Year and Date: 20091205-20091208
• [Presentation] Treatment with BortezomibOvercomes Resistance to Imatinib in Ph-Leukemia Quiescent Cells (2009)
  • Author(s): Kuwatsuka Y, Naoe T, et al.
  • Organizer: The American Society of Hematology 51th Annual Meeting
  • Place of Presentation: New Orleans USA
  • Year and Date: 20091205-20091208
• [Presentation] Double Genetic Mutations in PML-Rara Fusion Gene Confirmed in a Patient Showing Resistance to All-Trans Retinoic Acid and Arsenic-Trioxide Therapy (2009)
  • Author(s): Goto E, Naoe T, et al.
  • Organizer: The American Society of Hematology 51th Annual Meeting
  • Place of Presentation: New Orleans USA
  • Year and Date: 20091205-20091208
• [Presentation] FL-Dependent Wild-Type FLT3 Signals Reduce the Inhibitory Effects of FLT3 Inhibitors On Wild-Type and Mutant FLT3 Co-Expressing Cel (2009)
  • Author(s): Mori Y, Naoe T, et al.
  • Organizer: The American Society of Hematology 51th Annual Meeting
  • Place of Presentation: New Orleans USA
  • Year and Date: 20091205-20091208
• [Presentation] FLT3/ITD Regulates Leukemia Cell Adhesion throughα4β1 Integrin and Pyk2 Signalin (2009)
  • Author(s): Katsumi A, Naoe T, et al.
  • Organizer: The American Society of Hematology 51th Annual Meeting
  • Place of Presentation: New Orleans USA
  • Year and Date: 20091205-20091208
• [Presentation] Treatment with mTOR Inhibitor, Everolimus (RAD001) Overcomes Resistance to Imatinib in Ph-Leukemia Quiescent or T315I-Mutated Cells (2009)
  • Author(s): Minami Y, Naoe T, et al.
  • Organizer: The American Society of Hematology 51th Annual Meeting
  • Place of Presentation: New Orleans USA
  • Year and Date: 20091205-20091208
• [Patent(Industrial Property Rights)] 急性骨髄性白血病治療剤の候補物質を同定する方法 (2006)
  • Inventor(s): 直江知樹、早川文彦、岡本充功
  • Industrial Property Rights Holder: 国立大学法人名古屋大学
  • Industrial Property Number: 特許
  • Filing Date: 2006-06-02