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Analysis of ligand dependent resistance mechanism of RTK inhibitors

Research Project

Project/Area Number 24591387
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Hematology
Research InstitutionNagoya University

Principal Investigator

KIYOI Hitoshi  名古屋大学, 医学(系)研究科(研究院), 教授 (90314004)

Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords血液腫瘍学 / チロシンキナーゼ / 分子標的療法 / 白血病 / 耐性機構
Outline of Final Research Achievements

In this study, I analyzed the FLT3 ligand (FL)-dependent resistance mechanism of FLT3 inhibitors using wild type FLT3 (Wt-FLT3) and FLT3-ITD or extracellular domain-lacked FLT3-ITD (cyFLT3-ITD) co-expressing cells. I demonstrated that FL-stimulation activates co-expressing-Wt-FLT3 and MAPK, resulting in the reduction of anti-leukemia activity of FLT3 inhibitor. This FL-dependent inhibitory effect of FLT3 inhibitors was also confirmed in the human leukemia cell xenotransplant mouse models, in which Wt-FLT3 and FLT3-ITD co-expressing leukemia cells were not sufficiently eradicated by FLT3 inhibitors. These results also indicate that Wt-FLT3 expression level is a molecular marker for predicting the efficacy of FLT3 inhibitors.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Research-status Report
  • 2012 Research-status Report
  • Research Products

    (36 results)

All 2015 2014 2013 2012

All Journal Article (20 results) (of which Peer Reviewed: 20 results,  Open Access: 2 results) Presentation (16 results) (of which Invited: 5 results)

  • [Journal Article] FLT3 INHIBITORS: RECENT ADVANCES AND PROBLEMS FOR CLINICAL APPLICATION.2015

    • Author(s)
      Kiyoi H.
    • Journal Title

      Nagoya J Med Sci.

      Volume: 77 Pages: 7-17

    • NAID

      120005549547

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients2014

    • Author(s)
      Kihara R, S. Ogawa, S. (32/33) Naoe, T.
    • Journal Title

      Leukemia

      Volume: inpress Issue: 8 Pages: 1586-95

    • DOI

      10.1038/leu.2014.55

    • Related Report
      2014 Annual Research Report 2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Efficacy of ofatumumab against rituximab-resistant B-CLL/SLL cells with low CD20 protein expression.2014

    • Author(s)
      Shimada K, Tomita A, Saito S, Kiyoi H.
    • Journal Title

      Br J Haematol

      Volume: 165 Issue: 3 Pages: 455-7

    • DOI

      10.1111/bjh.12857

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Expression of CD56 is an unfavorable prognostic factor for acute promyelocytic leukemia with higher initial white blood cell counts.2014

    • Author(s)
      Ono T, Takeshita A, Kishimoto Y, Kiyoi H, Okada M, Yamauchi T, Emi N, Horikawa K, Matsuda M, Shinagawa K, Monma F, Ohtake S, Nakaseko C, Takahashi M, Kimura Y, Iwanaga M, Asou N, Naoe T; Japan Adult Leukemia Study Group.
    • Journal Title

      Cancer Sci

      Volume: 105 Issue: 1 Pages: 97-104

    • DOI

      10.1111/cas.12319

    • Related Report
      2013 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] De novo diffuse large B-cell lymphoma with a CD20 immunohistochemistry-positive and flow cytometry-negative phenotype: Molecular mechanisms and correlation with rituximab sensitivity.2014

    • Author(s)
      Tokunaga T, Tomita A, Sugimoto K, Shimada K, Iriyama C, Hirose T, Shirahata-Adachi M, Suzuki Y, Mizuno H, Kiyoi H, Asano N, Nakamura S, Kinoshita T, Naoe T.
    • Journal Title

      Cancer Sci.

      Volume: 105 Issue: 1 Pages: 35-43

    • DOI

      10.1111/cas.12307

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Leukemic evolution of donor-derived cells harboring IDH2 and DNMT3A mutations after allogeneic stem cell transplantation.2014

    • Author(s)
      Yasuda T, Ueno T, Fukumura K, Yamato A, Ando M, Yamaguchi H, Soda M, Kawazu M, Sai E, Yamashita Y, Murata M, Kiyoi H, Naoe T, Mano H.
    • Journal Title

      Leukemia

      Volume: 28 Issue: 2 Pages: 426-428

    • DOI

      10.1038/leu.2013.278

    • Related Report
      2013 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Role of hematopoietic stem cell transplantation for relapsed acute promyelocytic leukemia: a retrospective analysis of JALSG-APL97.2013

    • Author(s)
      Fujita H, Asou N, Iwanaga M, Hyo R, Nomura S, Kiyoi H, Okada M, Inaguma Y, Matsuda M, Yamauchi T, Ohtake S, Izumi T, Nakaseko C, Ishigatsubo Y, Shinagawa K, Takeshita A, Miyazaki Y, Ohnishi K, Miyawaki S, Naoe T; Japan Adult Leukemia Study Group.
    • Journal Title

      Cancer Sci

      Volume: 104 Issue: 10 Pages: 1339-1345

    • DOI

      10.1111/cas.12230

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] The demarcation between younger and older acute myeloid leukemia patients.2013

    • Author(s)
      Yanada M, Ohtake S, Miyawaki S, Sakamaki H, Sakura T, Maeda T, Miyamura K, Asou N, Oh I, Miyatake J, Kanbayashi H, Takeuchi J, Takahashi M, Dobashi N, Kiyoi H, Miyazaki Y, Emi N, Kobayashi Y, Ohno R, Naoe T.
    • Journal Title

      Cancer

      Volume: 119 Issue: 18 Pages: 3326-3333

    • DOI

      10.1002/cncr.28212

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] Mechanisms of action and resistance to all-trans retinoic acid (ATRA) and arsenic trioxide (As2O 3) in acute promyelocytic leukemia.2013

    • Author(s)
      Tomita A, Kiyoi H, Naoe T.
    • Journal Title

      Int J Hematol

      Volume: 97 Issue: 6 Pages: 717-725

    • DOI

      10.1007/s12185-013-1354-4

    • Related Report
      2013 Research-status Report
    • Peer Reviewed
  • [Journal Article] GATA2 zincfinger2mutationfoundinacutemyeloidleukemia impairs myeloiddifferentiation2013

    • Author(s)
      Keiko Niimi, Hitoshi Kiyoi, Yuichi Ishikawa, Fumihiko Hayakawa, Shingo Kurahashi, Rika Kihara, Akihiro Tomita, Tomoki Naoe
    • Journal Title

      Leukemia ResearchReports

      Volume: 2 Issue: 1 Pages: 21-25

    • DOI

      10.1016/j.lrr.2013.02.002

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Mutations in the nucleolar phosphoprotein, nucleophosmin, promote the expression of the oncogenic transcription factor MEF/ELF4 in leukemia cells and potentiates transformation.2013

    • Author(s)
      Ando K
    • Journal Title

      Journal of Biological Chemistry

      Volume: 288 Issue: 13 Pages: 9457-9467

    • DOI

      10.1074/jbc.m112.415703

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Gene mutations of acute myeloid leukemia in the genome era.2013

    • Author(s)
      Tomoki Naoe
    • Journal Title

      Int J Hematol

      Volume: 97 Issue: 2 Pages: 165-174

    • DOI

      10.1007/s12185-013-1257-4

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Long-term outcome and prognostic factors of elderly patients with acute promyelocytic leukemia2012

    • Author(s)
      Ono T, Takeshita A, Kishimoto Y, Kiyoi H, Okada M, Yamauchi T, Tsuzuki M, Horikawa K, Matsuda M, Shinagawa K, Monma F, Ohtake S, Nakaseko C, Takahashi M, Kimura Y, Iwanaga M, Asou N, Naoe T
    • Journal Title

      Cancer Sci.

      Volume: 103 Issue: 11 Pages: 174-1978

    • DOI

      10.1111/j.1349-7006.2012.02390.x

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Somatic mosaicism for oncogenic NRAS mutations in juvenile myelomonocytic leukemia2012

    • Author(s)
      Doisaki S, Muramatsu H, Shimada A, Takahashi Y, Mori-Ezaki M, Sato M, Kawaguchi H, Kinoshita A, Sotomatsu M, Hayashi Y, Furukawa-Hibi Y, Yamada K, Hoshino H, Kiyoi H, Yoshida N, Sakaguchi H, Narita A, Wang X, Ismael O, Xu Y, Nishio N, Tanaka M, Hama A, Koike K, Kojima S
    • Journal Title

      Blood

      Volume: 120 Issue: 7 Pages: 1485-1488

    • DOI

      10.1182/blood-2012-02-406090

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Randomized comparison of fixed-schedule versus response-oriented individualized induction therapy and use of ubenimex during and after consolidation therapy for elderly patients with acute myeloid leukemia: the JALSG GML200 Study2012

    • Author(s)
      Atsushi Wakita
    • Journal Title

      Int J Hematol

      Volume: 96 Issue: 1 Pages: 84

    • DOI

      10.1007/s12185-012-1105-y

    • NAID

      10030954605

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] CML cells expressing the TEL/MDS1/EVI1 fusion are resistant to imatinib-induced apoptosis through inhibition of BAD, but are resensitized with ABT-737.2012

    • Author(s)
      Shimada K, Tomita A, Minami Y, Kiyoi H, Naoe T et al.
    • Journal Title

      Exp Hematol.

      Volume: 40 Issue: 9 Pages: 724-737

    • DOI

      10.1016/j.exphem.2012.05.007

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Chimeric antisense RNA derived from chromosomal translocation modulates target gene expression.2012

    • Author(s)
      Takumi Sugimoto
    • Journal Title

      Haematologica

      Volume: 97 Issue: 8 Pages: 1278-1280

    • DOI

      10.3324/haematol.2011.057869

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Using peripheral blood circulating DNAs to detect CpG global methylation status and genetic mutations in patients with myelodysplastic syndrome2012

    • Author(s)
      Chisako Iriyama
    • Journal Title

      Biochem Biophys Res Commun

      Volume: (in press) Issue: 4 Pages: 662-669

    • DOI

      10.1016/j.bbrc.2012.02.071

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Long-term outcome of imatinib therapy, with assessment of its dosage and blood levels, for chronic myelogenous leukemia2012

    • Author(s)
      Ohnishi K, et al
    • Journal Title

      Cancer Science

      Volume: (In press) Issue: 6 Pages: 1071-1078

    • DOI

      10.1111/j.1349-7006.2012.02253.x

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Y654 of β-catenin is essential for FLT3/ITD-related tyrosine phosphorylation and nuclear localization of β-catenin2012

    • Author(s)
      Tomohiro Kajiguchi
    • Journal Title

      Eur J Haematol

      Volume: (in press) Issue: 4 Pages: 314-320

    • DOI

      10.1111/j.1600-0609.2011.01738.x

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Presentation] Mechanism of FLT3 Ligand Dependent Resistance to FLT3 Inhibitors2014

    • Author(s)
      Fangli Chen,Yuichi Ishikawa,Akimi Akashi,Tomoki Naoe,Hitoshi Kiyoi
    • Organizer
      第56回米国血液学会
    • Place of Presentation
      サンフランシスコ、米国
    • Year and Date
      2014-12-06 – 2014-12-09
    • Related Report
      2014 Annual Research Report
  • [Presentation] Mechanism of FLT3 ligand dependent resistance to FLT3 inhibitors2014

    • Author(s)
      陳昉里、石川裕一、直江知樹、清井仁
    • Organizer
      第76回日本血液学会学術集会
    • Place of Presentation
      大阪国際会議場 大阪府 大阪市
    • Year and Date
      2014-10-31 – 2014-11-02
    • Related Report
      2014 Annual Research Report
  • [Presentation] 共発現する正常受容体型チロシンキナーゼ(RTK)のリガンド依存性シグナルを介した阻害剤の効果減弱機構2014

    • Author(s)
      鈴木弘太郎、石川裕一、清井 仁
    • Organizer
      第73回日本癌学会学術総会
    • Place of Presentation
      パシフィコ横浜 神奈川県 横浜市
    • Year and Date
      2014-09-25 – 2014-09-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] Mechanism of FLT3 Ligand dependent resistance to FLT3 inhibitors2014

    • Author(s)
      陳昉里、石川裕一、木原里香、直江知樹、清井仁
    • Organizer
      第35回国際血液学会
    • Place of Presentation
      北京 中国
    • Year and Date
      2014-09-04 – 2014-09-07
    • Related Report
      2014 Annual Research Report
  • [Presentation] 活性型変異FLT3を標的とした白血病治療の現状と課題2014

    • Author(s)
      清井仁
    • Organizer
      第23回日本Cell Death学会学術集会
    • Place of Presentation
      東京医科歯科大学 鈴木章夫記念講堂 東京都 文京区
    • Year and Date
      2014-07-18 – 2014-07-19
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Inhibitory effects of FL on proliferation and FLT3 inhibitors in Wt- and ITD-FLT3-co-expressing cells2014

    • Author(s)
      陳昉里、石川裕一、木原里香、清井仁
    • Organizer
      第5回日本血液学会(JSH)国際シンポジウム
    • Place of Presentation
      アクトシティ浜松 コングレスセンター 静岡県 浜松市
    • Year and Date
      2014-05-24 – 2014-05-25
    • Related Report
      2014 Annual Research Report
  • [Presentation] Comprehensive Analysis of Genetic Alterations and Their Prognostic Impacts in Adult Acute Myeloid Leukemia Patients Treated with the Japan Adult Leukemia Study2014

    • Author(s)
      Hitoshi Kiyoi, RiKa Kihara,Yasunobu Nagata, Seishi Ogawa,Tomoki Naoe.
    • Organizer
      第5回日本血液学会(JSH)国際シンポジウム
    • Place of Presentation
      アクトシティ浜松 コングレスセンター 静岡県 浜松市
    • Year and Date
      2014-05-24 – 2014-05-25
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Prognostic Re-Classification of Adult Acute Myeloid Leukemia Based on the Comprehensive Genetic Analysis2013

    • Author(s)
      1) 清井仁、木原里香、鈴木弘太郎、陳昉里、加藤貴大、山本絵里奈、直江知樹、小川誠司、永田安伸、麻生範雄、大竹茂樹、宮脇修一、宮崎泰司、佐倉徹、小澤幸泰、薄井紀子、金森平和、木口亨、今井陽俊、鵜池直邦、木村文彦、北村邦朗、中世古千昭、坪井康介、竹下明裕、石田文宏、鈴島仁、加藤裕一、三輪啓志
    • Organizer
      The 18th Congress of EHA
    • Place of Presentation
      ストックホルム(スウェーデン)
    • Related Report
      2013 Research-status Report
  • [Presentation] Prognostic impacts and clonal heterogeneity of recurrently identified mutations in AML2013

    • Author(s)
      清井仁
    • Organizer
      XXVI Symposium IACRLRD
    • Place of Presentation
      トリノ(イタリア)
    • Related Report
      2013 Research-status Report
    • Invited
  • [Presentation] 正常及び変異FLT3共発現細胞の細胞増殖及びFLT3阻害剤効果に対するFLの抑制効果2013

    • Author(s)
      陳昉里、清井仁、直江知樹、木原里香、直江知樹
    • Organizer
      第75回日本血液学会学術集会
    • Place of Presentation
      ロイトン札幌
    • Related Report
      2013 Research-status Report
  • [Presentation] 急性骨髄性白血病における分子標的治療薬の開発2012

    • Author(s)
      清井 仁
    • Organizer
      第54回日本小児血液・がん学会学術集会
    • Place of Presentation
      パシフィコ横浜
    • Related Report
      2012 Research-status Report
    • Invited
  • [Presentation] 白血病治療の現状と将来2012

    • Author(s)
      清井 仁
    • Organizer
      第50回日本癌治療学会総会
    • Place of Presentation
      パシフィコ横浜
    • Related Report
      2012 Research-status Report
    • Invited
  • [Presentation] Allogeneic Stem Cell Transplantation at the Primary Induction Failure or after the 1st Relapse Dose not Conquer Poor Prognosis of AML with FLT3-ITD.2012

    • Author(s)
      Rika Kihara
    • Organizer
      第3回日本血液学会国際シンポジウム
    • Place of Presentation
      川越プリンスホテル
    • Related Report
      2012 Research-status Report
  • [Presentation] ELN分子層別化システムに基づいたJALSG AML201登録患者の予後2012

    • Author(s)
      木原里香
    • Organizer
      第71回日本癌学会学術総会
    • Place of Presentation
      ロイトン札幌
    • Related Report
      2012 Research-status Report
  • [Presentation] Evaluation of the ELN genetic risk classification in AML patients registered to JALSG AML201 study.2012

    • Author(s)
      木原里香
    • Organizer
      第74回日本血液学会学術集会
    • Place of Presentation
      京都国際会議場
    • Related Report
      2012 Research-status Report
  • [Presentation] A Collaborative Study of the Japan Adult Leukemia Study Group and the Korean Society of Hematology.2012

    • Author(s)
      Tomohiro Taki
    • Organizer
      第54回アメリカ血液学会
    • Place of Presentation
      Atlanta
    • Related Report
      2012 Research-status Report

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Published: 2013-05-31   Modified: 2019-07-29  

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