白血病に選択性を有する分子標的治療法ならびにその評価法の開発

• 研究課題/領域番号: 17016029
• 研究種目: 特定領域研究
• 配分区分: 補助金
• 審査区分: 生物系
• 研究機関: 名古屋大学
• 研究代表者: 直江 知樹 名古屋大学, 大学院・医学系研究科, 教授 (50217634)
• 研究期間 (年度): 2005 – 2009
• 研究課題ステータス: 完了 (2009年度)
• 配分額: 45,900千円 (直接経費: 45,900千円); 2009年度: 9,100千円 (直接経費: 9,100千円); 2008年度: 9,100千円 (直接経費: 9,100千円); 2007年度: 9,100千円 (直接経費: 9,100千円); 2006年度: 9,100千円 (直接経費: 9,100千円); 2005年度: 9,500千円 (直接経費: 9,500千円)
• キーワード: 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 / FLT3 / STAT / 急性前骨髄球性白血病 / マウスモデル / 急性前骨髓球性白血病 / PML-RARα / 転写抑制複合体 / キメラ転写物 / 転写抑制 / 免疫不全マウス / 治療法

研究概要

白血病に対する有効で安全性の高い標的治療の開発のため、1) 白血病に特異的な分子病態と標的分子の同定を行い、変異FLT3や変異KIT、さらにキメラ転写因子PML-RARAにリクルートされるN-CoR/HDAC3/TBLR1複合体が新たな標的分子となり得ることを明らかにした。2) 標的のための阻害剤開発を行い、FLT3阻害剤としてFI-700、KW-2449、KIT阻害剤としてKI-328を開発した。N-CoR/HDAC3/TBLR1複合体に対してはデコイペプチドの開発を行った。3) チロシンキナーゼ阻害剤の評価系として、p-FLT3あるいはp-STAT5に対する抗体によるFACSおよび血漿バイオアッセイ系を確立した。

研究成果

• [雑誌論文] 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)
  • 著者名/発表者名: 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
  • 雑誌名: Eur J Haematol 84 ページ: 229-38
  • 査読あり
• [雑誌論文] Irrespective of CD34 expression, lineage-committed cell fraction reconstitutes and re-establishes transformed Philadelphia chromosome-positive leukemia in NOD/SCID/IL-2Rgammac mice. (2010)
  • 著者名/発表者名: Tanizaki R, et al.
  • 雑誌名: Cancer Sci 16(in press)
  • 査読あり
• [雑誌論文] KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation (2009)
  • 著者名/発表者名: 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.
  • 雑誌名: Blood. 114 ページ: 1607-17
  • 査読あり
• [雑誌論文] Comprehensive analysis of cooperative gene mutations between class I and class II in de novo acute myeloid leukemia (2009)
  • 著者名/発表者名: Ishikawa Y, Kiyoi H, Tsujimura A, Miyawaki S, Miyazaki Y, Kuriyama K, Tomonaga M, Naoe T.
  • 雑誌名: Eur J Haematol 83 ページ: 90-8
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: 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.
  • 雑誌名: Leukemia. 23 ページ: 1270-7
  • 査読あり
• [雑誌論文] BCR-ABL-independent and RAS/MAPK pathway-dependent form of imatinib resistance in Ph-positive acute lymphoblastic leukemia cell line with activation of EphB4. (2009)
  • 著者名/発表者名: Suzuki M, et al.
  • 雑誌名: Eur J Haematol 84 ページ: 229-238
  • 査読あり
• [雑誌論文] KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemi a cells with FLT3 mutations or T315I-mutated BCR/ABL translocation (2009)
  • 著者名/発表者名: Suhiotsu, et al.
  • 雑誌名: Blood 114 ページ: 1607-1617
  • 査読あり
• [雑誌論文] Retention but significant reduction of BCR-ABL transcript in hematopoietic stem cells in chronic myelogenous leukemia after imatinib therapy (2008)
  • 著者名/発表者名: Abe A, Minami Y, Hayakawa F, Kitamura K, Nomura Y, Murata M, Katsumi A, Kiyoi H, Jamieson CH, Wang JY, Naoe T.
  • 雑誌名: Int J Hematol. 88 ページ: 471-5
  • NAID: 10023971017
  • 査読あり
• [雑誌論文] BCR-ABL-transformed GMP as myeloid leukemic stem cells (2008)
  • 著者名/発表者名: Minami Y, Stuart SA, Ikawa T, Jiang Y, Banno A, Hunton IC, Young DJ, Naoe T, Murre C, Jamieson CH, Wang JY.
  • 雑誌名: Proc Natl Acad Sci U S A 105 ページ: 17967-72
  • 査読あり
• [雑誌論文] Prognostic implication and biological roles of RhoH in acute myeloid leukaemia (2008)
  • 著者名/発表者名: 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.
  • 雑誌名: Eur J Haematol 81 ページ: 454-60
  • 査読あり
• [雑誌論文] Clinical significance of nuclear non-phosphorylated beta-catenin in acute myeloid leukaemia and myelodysplastic syndrome (2008)
  • 著者名/発表者名: Xu J, Suzuki M, Niwa Y, Hiraga J, Nagasaka T, Ito M, Nakamura S, Tomita A, Abe A, Kiyoi H, Kinoshita T, Naoe T.
  • 雑誌名: Br J Haematol. 140 ページ: 394-401
  • 査読あり
• [雑誌論文] Acetylation of PML is involved in histone deacetylase inhibitor-mediated apoptosis (2008)
  • 著者名/発表者名: Hayakawa F, Naoe T, et.al.
  • 雑誌名: J Biol Chem. 283 ページ: 24420-5
  • 査読あり
• [雑誌論文] BCR-ABL-transformed GMP as myeloid leukemic stem cells (2008)
  • 著者名/発表者名: Minami Y and Naoe T, et.al.
  • 雑誌名: Proc Natl Acad Sci USA. 105 ページ: 17967-72
  • 査読あり
• [雑誌論文] Novel and orally active 5-(1,3,4-oxadiazol-2-yl)pyrimidine derivatives as selective FLT3 inhibitors (2008)
  • 著者名/発表者名: Ishida H and Naoe T, et.al.
  • 雑誌名: Bioorg Med Chem Lett. 18 ページ: 5472-7
  • 査読あり
• [雑誌論文] FLT3 regulates beta-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells (2007)
  • 著者名/発表者名: Kajiguchi T, Chung EJ, Lee S, Stine A, Kiyoi H, Naoe T, Levis MJ, Neckers L, Trepel JB.
  • 雑誌名: Leukemia 21 ページ: 2476-84
  • 査読あり
• [雑誌論文] A novel FLT3 inhibitor FI-700 selectively suppresses the growth of leukemia cells with FLT3 mutations (2007)
  • 著者名/発表者名: Kiyoi H, Shiotsu Y, Ozeki K, Yamaji S, Kosugi H, Umehara H, Shimizu M, Arai H, Ishii K, Akinaga S, Naoe T.
  • 雑誌名: Clin Cancer Res. 13(15Pt1) ページ: 4575-82
  • 査読あり
• [雑誌論文] PML-retinoic acid receptor alpha inhibits PML IV enhancement of PU. 1-induced C/EBPepsilon expression in myeloid differentiation (2007)
  • 著者名/発表者名: Yoshida H, Ichikawa H, Tagata Y, Katsumoto T, Ohnishi K, Akao Y, Naoe T, Pandolfi PP, Kitabayashi I.
  • 雑誌名: Mol Cell Biol 27 ページ: 5819-34
  • 査読あり
• [雑誌論文] LRP16 is fused to RUNX1 in monocytic leukemia cell line with t(11;21)(q13;q22) (2007)
  • 著者名/発表者名: Imagama S, Abe A, Suzuki M, Hayakawa F, Katsumi A, Emi N, Kiyoi H, Naoe T.
  • 雑誌名: Eur J Haematol. 79 ページ: 25-31
  • 査読あり
• [雑誌論文] JAK3 mutations occur in acute megakaryoblastic leukemia both in Down syndrome children and non-Down syndrome adults (2007)
  • 著者名/発表者名: Kiyoi H, Yamaji S, Kojima S, Naoe T.
  • 雑誌名: Leukemia 21 ページ: 574-6
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: Okamoto M, Hayakawa F, Miyata Y, Watamoto K, Emi N, Abe A, Kiyoi H, Towatari M, Naoe T.
  • 雑誌名: Leukemia 21 ページ: 403-10
  • 査読あり
• [雑誌論文] Homing, proliferation and survival sites of human leukemia cells in vivo in immunodeficient mice (2007)
  • 著者名/発表者名: Ninomiya M, Abe A, Katsumi A, Xu J, Ito M, Arai F, Suda T, Ito M, Kiyoi H, Kinoshita T, Naoe T.
  • 雑誌名: Leukemia 21 ページ: 136-42
  • 査読あり
• [雑誌論文] FLT3 regulates beta-catenin tyrosine phosphorylation, nuclear localization, and transcriptional activity in acute myeloid leukemia cells. (2007)
  • 著者名/発表者名: Tomohiro Kajiguchi
  • 雑誌名: Leukemia. 21 ページ: 2476-84
  • 査読あり
• [雑誌論文] A novel FLT3 inhibitor FI-700 selectively suppresses the growth of leukemia cells with FLT3 mutations. (2007)
  • 著者名/発表者名: Hitoshi Kiyoi
  • 雑誌名: Clin Cancer Res. 13 ページ: 4575-82
  • 査読あり
• [雑誌論文] Prediction of risk of disease recurrence by genome-wide cDNA microarray analysis in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with imatinib-combined chemotherapy. (2007)
  • 著者名/発表者名: Hitoshi Zembutsu
  • 雑誌名: Int J Oncol. 31 ページ: 313-22
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: Mitsunori Okamoto
  • 雑誌名: Leukemia 21 ページ: 403-410
• [雑誌論文] Establishment of a stroma-dependent human acute myelomonocytic leukemia cell line, NAMO-2, with FLT3 tandem duplication (2006)
  • 著者名/発表者名: Abe A, Kiyoi H, Ninomiya M, Yamazaki T, Murase T, Ozeki K, Suzuki M, Hayakawa F, Katsumi A, Emi N, Naoe T.
  • 雑誌名: Int J Hematol 84 ページ: 328-36
  • NAID: 10019259671
  • 査読あり
• [雑誌論文] Biology, clinical relevance, and molecularly targeted therapy in acute leukemia with FLT3 mutation (2006)
  • 著者名/発表者名: Kiyoi H, Naoe T.
  • 雑誌名: Int J Hematol 83 ページ: 301-8
  • NAID: 10017475435
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: Atsumi A, Tomita A, Kiyoi H, Naoe T.
  • 雑誌名: Biochem Biophys Res Commun. 345 ページ: 1471-80
  • 査読あり
• [雑誌論文] PTPN11, RAS and FLT3 mutations in childhood acute lymphoblastic leukemia (2006)
  • 著者名/発表者名: Yamamoto T, Isomura M, Xu Y, Liang J, Yagasaki H, Kamachi Y, Kudo K, Kiyoi H, Naoe T, Kojma S.
  • 雑誌名: Leuk Res. 30 ページ: 1085-9
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: Suzuki M, Abe A, Kiyoi H, Murata M, Ito Y, Shimada K, Morishita Y, Kinoshita T, Naoe T.
  • 雑誌名: Leukemia 20 ページ: 1168-9
  • 査読あり
• [雑誌論文] 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)
  • 著者名/発表者名: 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
  • 雑誌名: J Clin Oncol. 24 ページ: 460-6
  • 査読あり
• [雑誌論文] SFK-STAT Pathway : An Alternative and Important Way to Malignancies. (2006)
  • 著者名/発表者名: Fumihiko Hayakawa
  • 雑誌名: Ann N Y Acad Sci 1086 ページ: 213-222
• [雑誌論文] Histone deacetylase 3 (HDAC3) is recruited to target promoters by PML-RARalpha as a component of the N-CoR co-repressor complex to regress transcription in vivo. (2006)
  • 著者名/発表者名: Akihide Atsumi
  • 雑誌名: Biochem Biophys Res Commu 345(4) ページ: 1471-1480
• [雑誌論文] 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)
  • 著者名/発表者名: Momoko Suzuki
  • 雑誌名: Leukemia 20(6) ページ: 1168-1169
• [雑誌論文] Genomewide array-based comparative genomic hybridization analysis of acute promyelocytic leukemia. (2006)
  • 著者名/発表者名: Sivasundaram Karnan
  • 雑誌名: Genes Chromosomes Cancer 45(4) ページ: 420-425
• [雑誌論文] 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)
  • 著者名/発表者名: Masamitsu Yanada
  • 雑誌名: J Clin Oncol 24(3) ページ: 460-466
• [雑誌論文] BMI-1 is highly expressed in M0-subtype acute myeloid leukemia. (2005)
  • 著者名/発表者名: 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.
  • 雑誌名: Int J Hematol 82 ページ: 42-7
  • NAID: 10016602887
  • 査読あり
• [雑誌論文] Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia (2005)
  • 著者名/発表者名: 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.
  • 雑誌名: Blood 106 ページ: 2854-61
  • 査読あり
• [雑誌論文] Efficacy of gemtuzumab ozogamicin on ATRA- and arsenic-resistant acute promyelocytic leukemia (APL) cells (2005)
  • 著者名/発表者名: Takeshita A, Shinjo K, Naito K, Matsui H, Sahara N, Shigeno K, Horii T, Shirai N, Maekawa M, Ohnishi K, Naoe T, Ohno R.
  • 雑誌名: Leukemia 19 ページ: 1306-11
  • 査読あり
• [雑誌論文] BMI-1 is highly expressed in MO-subtype acute myeloid leukemia. (2005)
  • 著者名/発表者名: Masashi Sawa
  • 雑誌名: Int J Hematol 82(1) ページ: 42-47
• [雑誌論文] Clinical characteristics and prognostic implications of NPM1 mutations in acute myeloid leukemia. (2005)
  • 著者名/発表者名: Tatsuya Suzuki
  • 雑誌名: Blood 106(8) ページ: 2854-2861
• [雑誌論文] Efficacy of gemtuzumab ozogamicin on ATRA- and arsenic-resistant acute promyelocytic leukemia (APL) cells. (2005)
  • 著者名/発表者名: Akihiro Takeshita
  • 雑誌名: Leukemia 19(8) ページ: 1306-1311
• [雑誌論文] Expression and methylation status of the FHIT gene in acute myeloid leukemia and myelodysplastic syndrome. (2005)
  • 著者名/発表者名: Masanori Iwai
  • 雑誌名: Leukemia 19(8) ページ: 1376-1375
• [雑誌論文] Increased erythropoietin level and reticulocyte count during arsenic trioxide therapy. (2005)
  • 著者名/発表者名: Tomohiro Kajiguchi
  • 雑誌名: Leukemia 19(4) ページ: 674-676
• [雑誌論文] Irrespective of CD34 expression, lineage-committed cell fraction reconstitutes and re-establishes transformed Philadelphia chromosome-positive leukemia in NOD / SCID / IL-2Rgammac mice
  • 著者名/発表者名: Tanizaki R, Naoe T., et al.
  • 雑誌名: Cancer Sci. 2009(in Press)
  • 査読あり
• [学会発表] 新規KIT選択的阻害剤KI-328の抗白血病細胞効果の検討 (2009)
  • 著者名/発表者名: Tsujimura, et al.
  • 学会等名: 日本血液学会
  • 発表場所: 京都
  • 年月日: 2009-10-23
• [学会発表] 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)
  • 著者名/発表者名: Sugimoto T, Naoe T, et al.
  • 学会等名: The American Society of Hematology 51th Annual Meeting
  • 発表場所: New Orleans USA
• [学会発表] Treatment with BortezomibOvercomes Resistance to Imatinib in Ph-Leukemia Quiescent Cells (2009)
  • 著者名/発表者名: Kuwatsuka Y, Naoe T, et al.
  • 学会等名: The American Society of Hematology 51th Annual Meeting
  • 発表場所: New Orleans USA
• [学会発表] Double Genetic Mutations in PML-Rara Fusion Gene Confirmed in a Patient Showing Resistance to All-Trans Retinoic Acid and Arsenic-Trioxide Therapy (2009)
  • 著者名/発表者名: Goto E, Naoe T, et al.
  • 学会等名: The American Society of Hematology 51th Annual Meeting
  • 発表場所: New Orleans USA
• [学会発表] FL-Dependent Wild-Type FLT3 Signals Reduce the Inhibitory Effects of FLT3 Inhibitors On Wild-Type and Mutant FLT3 Co-Expressing Cel (2009)
  • 著者名/発表者名: Mori Y, Naoe T, et al.
  • 学会等名: The American Society of Hematology 51th Annual Meeting
  • 発表場所: New Orleans USA
• [学会発表] FLT3/ITD Regulates Leukemia Cell Adhesion throughα4β1 Integrin and Pyk2 Signalin (2009)
  • 著者名/発表者名: Katsumi A, Naoe T, et al.
  • 学会等名: The American Society of Hematology 51th Annual Meeting
  • 発表場所: New Orleans USA
• [学会発表] Treatment with mTOR Inhibitor, Everolimus (RAD001) Overcomes Resistance to Imatinib in Ph-Leukemia Quiescent or T315I-Mutated Cells (2009)
  • 著者名/発表者名: Minami Y, Naoe T, et al.
  • 学会等名: The American Society of Hematology 51th Annual Meeting
  • 発表場所: New Orleans USA
• [学会発表] KW-2449, a Novel Multi-Kinase Inhibitor, Suppresses the Growth of Imatinib-Resistant Ph+ Leukemia Including BCR-ABL/T315I Both in Vitro and in Vivo (2008)
  • 著者名/発表者名: Shiotsu Y and Naoe T, et.al.
  • 学会等名: ASH Annual Meeting 2008
  • 発表場所: San Francisco, USA
  • 年月日: 2008-12-08
• [産業財産権] 急性骨髄性白血病治療剤の候補物質を同定する方法 (2006)
  • 発明者名: 直江知樹、早川文彦、岡本充功
  • 権利者名: 国立大学法人名古屋大学
  • 出願年月日: 2006-06-02
• [産業財産権] 急性骨髄性白血病治療剤の候補物質を同定する方法 (2006)
  • 発明者名: 直江知樹, 早川文彦, 岡本充功
  • 権利者名: 名古屋大学
  • 産業財産権番号: 2006-155281
  • 出願年月日: 2006-06-02