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Molecular mechanism of refractoriness of myeloma mediated by adhesion molecules

Research Project

Project/Area Number 23591409
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Hematology
Research InstitutionTokyo Women's Medical University

Principal Investigator

IMAI Yoichi  東京女子医科大学, 医学部, 講師 (10345209)

Co-Investigator(Renkei-kenkyūsha) MARU Yoshiro  東京女子医科大学, 医学部, 教授 (00251447)
Project Period (FY) 2011 – 2013
Project Status Completed (Fiscal Year 2013)
Budget Amount *help
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2013: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Keywords血液腫瘍学 / 多発性骨髄腫 / 接着分子 / カルシニューリン / 国際情報交換 / インテグリン / CXCR4 / HDAC阻害剤 / HOXA9 / 増殖抑制 / アポトーシス
Research Abstract

Multiple myeloma is one of incurable hematological malignancies. We revealed that functional inhibition of integrin and histone deacetylase (HDAC) blocks proliferation and induces apoptosis in myeloma cells. We discovered that MLL-HOXA9 and PPP3CA, alfa subunit of calcineurin, are inhibited by HDAC inhibitors. We revealed that MLL and PPP3CA are protected from protein degradation by HSP90. HDAC inhibitors induce degradation of MLL and PPP3CA through inhibition of chaperone function of HSP90. It was shown that PPP3CA plays important roles in maintenance of viability of myeloma cells in vitro and in vivo. In clinical samples, PPP3CA expression was high in advanced disease. Osteoclasts formation is essential for osteolytic disease of multiple myeloma. PPP3CA was necessary for formation of osteoclasts and HDAC inhibitors were shown to inhibit osteoclasts formation.

Report

(4 results)
  • 2013 Annual Research Report   Final Research Report ( PDF )
  • 2012 Research-status Report
  • 2011 Research-status Report
  • Research Products

    (25 results)

All 2014 2013 2012 2011

All Journal Article (16 results) (of which Peer Reviewed: 3 results) Presentation (7 results) Book (2 results)

  • [Journal Article] A case report of donor cell-derived leukemia after cord blood transplantation and a review of the literature : differences from bone marrow as the transplanted source2014

    • Author(s)
      Shiozaki H, Yoshinaga K, Kondo T, Imai Y, Shiseki M, Mori N, Teramura M, Motoji T
    • Journal Title

      Bone Marrow Transplantation

      Volume: 49 Pages: 102-109

    • Related Report
      2013 Final Research Report
  • [Journal Article] Identification of calcineurin as a novel therapeutic target in multiple myeloma2013

    • Author(s)
      Imai Y, Ohta E, Wang Y, Kitagawa Y, Ding Y, Yamada O, Maru Y, Motoji T
    • Journal Title

      Clinical Lymphoma, Myeloma, & Leukemia

      Volume: 13

    • Related Report
      2013 Final Research Report
  • [Journal Article] Transient lupus anticoagulant with a prolonged activated partial thromboplastin time secondary to cytomegalovirus-related infectious mononucleosis2013

    • Author(s)
      Shimura H, Imai Y, Ieko M, Shiseki M, Mori N, Teramura M, Motoji T
    • Journal Title

      Annals of Hematology

      Volume: 2 Pages: 143-144

    • Related Report
      2013 Final Research Report
  • [Journal Article] Identification of calcineurin as a novel therapeutic target in multiple myeloma.2013

    • Author(s)
      Imai Y, Ohta E, Wang Y, Kitagawa Y, Ding Y, Yamada O, Maru Y, Motoji T
    • Journal Title

      Clinical Lymphoma, Myeloma, & Leukemia

      Volume: 13 supplement 1 Pages: 47-47

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] MLL-HOXA9 and calcineurin are novel therapeutic targets in multiple myeloma2012

    • Author(s)
      Imai Y, Ohta E, Wang Y, Kitagawa Y, Ding Y, Yamada O, Maru Y, Motoji T
    • Journal Title

      American Society of Hematology annual meeting abstracts

      Volume: 120 Pages: 4007-4007

    • Related Report
      2013 Final Research Report
  • [Journal Article] Multiple phosphorylation sites are important for RUNX1 activity in early hematopoiesis and T-cell differentiation2012

    • Author(s)
      Yoshimi M, Goyama S, Kawazu M, Nakagawa M, Ichikawa M, Imai Y, Kumano K, Asai T, Mulloy JC, Kraft AS, Takahashi T, Shirafuji N, Kurokawa M
    • Journal Title

      European Journal of Immunology

      Volume: 42 Pages: 1044-1050

    • Related Report
      2013 Final Research Report
  • [Journal Article] The effect of iron overload and chelation on erythroid differentiation2012

    • Author(s)
      Taoka K, Kumano K, Nakamura F, Hosoi M, Goyama S, Imai Y, Hangaishi A, Kurokawa M
    • Journal Title

      International Journal of Hematology

      Volume: 95 Pages: 149-159

    • NAID

      10030267276

    • Related Report
      2013 Final Research Report
  • [Journal Article] Combined romiplostim and intravenous immunoglobulin therapy increased platelet count, facilitating splenectomy in a patient with refractory immune thrombocytopenic purpura unresponsive to monotherapy2012

    • Author(s)
      Mitsuhashi K, Ishiyama M, Imai Y, Shiseki M, Mori N, Teramura M, Seshimo A, Motoji T
    • Journal Title

      British Journal of Haematology

      Volume: 158 Pages: 798-800

    • Related Report
      2013 Final Research Report
  • [Journal Article] Evi1 is essential for hematopoietic stem cell self-renewal, and its expression marks hematopoietic cells with long-term multilineage repopulating activity2011

    • Author(s)
      Kataoka K, Sato T, Yoshimi A, Goyama S, Tsuruta T, Kobayashi H, Shimabe M, Arai S, Nakagawa M, Imai Y, Kumano K, Kumagai K, Kubota, N, Kadowaki T, Kurokawa M
    • Journal Title

      Journal of Experimental Medicine

      Volume: 208 Pages: 2403-2416

    • Related Report
      2013 Final Research Report
  • [Journal Article] AML1/RUNX1 functions as a cytoplasmic attenuator of NF-kB signaling in the repression of myeloid tumors2011

    • Author(s)
      Nakagawa M, Shimabe M, Watanabe-Okochi N, Arai S, Yoshimi A, Shinohara A, Nishimoto N, Kataoka K, Sato T, Kumano K, Nannya Y, Ichikawa M, Imai Y, Kurokawa M
    • Journal Title

      Blood

      Volume: 118 Pages: 6626-6637

    • Related Report
      2013 Final Research Report
  • [Journal Article] Loss of AML1/Runx1 accelerates the development of MLL-ENL leukemia through down-regulation of p19^<ARF>2011

    • Author(s)
      Nishimoto N, Arai S, Ichikawa M, Nakagawa M, Goyama S, Kumano K, Takahashi T, Kamikubo Y, Imai Y, Kurokawa M
    • Journal Title

      Blood

      Volume: 118 Pages: 2541-2550

    • Related Report
      2013 Final Research Report
  • [Journal Article] The negative impact of female donor/male recipient combination in allogeneic hematopoietic stem cell transplantation depends on disease risk2011

    • Author(s)
      Nannya Y, Kataoka K, Hangaishi A, Imai Y, Takahashi T, Kurokawa M
    • Journal Title

      Transplant International

      Volume: 24 Pages: 469-476

    • Related Report
      2013 Final Research Report
  • [Journal Article] Evi-1 is a transcriptional target of mixed-lineage leukemia oncoproteins in hematopoietic stem cells2011

    • Author(s)
      Arai S, Yoshimi A, Shimabe M, Ichikawa M, Nakagawa M, Imai Y, Goyama S, Kurokawa M
    • Journal Title

      Blood

      Volume: 117 Pages: 6304-6314

    • Related Report
      2013 Final Research Report
  • [Journal Article] Evi1 represses PTEN expression and activates PI3K/AKT/mTOR via interactions with polycomb proteins2011

    • Author(s)
      Yoshimi A, Goyama S, Watanabe-Okochi N, Yoshiki Y, Nannya Y, Nitta E, Arai S, Sato T, Shimabe M, Nakagawa M, Imai Y, Kitamura T, Kurokawa M
    • Journal Title

      Blood

      Volume: 117 Pages: 3617-3628

    • Related Report
      2013 Final Research Report
  • [Journal Article] AML1/RUNX1 functions as a cytoplasmic attenuator of NF-κB signaling in the repression of myeloid tumors2011

    • Author(s)
      Masahiro Nakagawa
    • Journal Title

      Blood

      Volume: 118 Issue: 25 Pages: 6626-6637

    • DOI

      10.1182/blood-2010-12-326710

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Journal Article] Loss of AML1/Runx1 accelerates the development of MLL-ENL leukemia through downregulation of p19ARF2011

    • Author(s)
      黒川峰夫, 他
    • Journal Title

      Blood

      Volume: 118 Issue: 9 Pages: 2541-2550

    • DOI

      10.1182/blood-2010-10-315440

    • Related Report
      2011 Research-status Report
    • Peer Reviewed
  • [Presentation] Identification of calcineurin as a novel therapeutic target in multiple myeloma2013

    • Author(s)
      Imai Y, Ohta E, Wang Y, Kitagawa Y, Ding Y, Yamada O, Maru Y, Motoji T
    • Organizer
      14th International Myeloma Workshop
    • Place of Presentation
      Kyoto
    • Year and Date
      2013-04-04
    • Related Report
      2013 Final Research Report
  • [Presentation] Identification of calcineurin as a novel therapeutic target in multiple myeloma.2013

    • Author(s)
      Imai Y, Ohta E, Wang Y, Kitagawa Y, Ding Y, Yamada O, Maru Y, Motoji T
    • Organizer
      14th International Myeloma Workshop
    • Place of Presentation
      京都
    • Related Report
      2013 Annual Research Report
  • [Presentation] Identification of Calcineurin as a Novel Therapeutic Target in Multiple Myeloma2013

    • Author(s)
      Yoichi Imai, Eri Ohta, Yanhua Wang, Yukiko Kitagawa, Ye Ding, Osamu Yamda, Yoshiro Maru, and Toshiko Motoji
    • Organizer
      14th International Myeloma Workshop
    • Place of Presentation
      京都
    • Related Report
      2012 Research-status Report
  • [Presentation] MLL-HOXA9 and calcineurin are novel therapeutic targets in multiple myeloma2012

    • Author(s)
      Imai Y, Ohta E, Wang Y, Kitagawa Y, Ding Y, Yamada O, Maru Y, Motoji T
    • Organizer
      54th American Society of Hematology Annual Meeting
    • Place of Presentation
      Atlanta, December
    • Related Report
      2013 Final Research Report
  • [Presentation] Elucidation of MLL as a novel therapy target and molecular mechanism of inhibitors of HDAC and HSP90 in multiple myeloma2012

    • Author(s)
      Yoichi Imai, Eri Ohta, Yanhua Wang, Ye Ding, Osamu Yamda, Yoshiro Maru, and Toshiko Motoji
    • Organizer
      日本骨髄腫学会総会
    • Place of Presentation
      京都
    • Related Report
      2012 Research-status Report
  • [Presentation] MLL is a novel target of anti-myeloma therapy and it is degraded by inhibitors of histone deacetylase (HDAC) and HSP90.2012

    • Author(s)
      Yoichi Imai, Eri Ohta, Yanhua Wang, Ye Ding, Osamu Yamada, Yoshiro Maru, and Toshiko Motoji
    • Organizer
      日本血液学会総会
    • Place of Presentation
      京都
    • Related Report
      2012 Research-status Report
  • [Presentation] MLK-HOXA9 and Calcineurin are Novel Therapeutic Targets in Multiple Myeloma2012

    • Author(s)
      Yoichi Imai, Eri Ohta, Yanhua Wang, Yukiko Kitagawa, Ye Ding, Osamu Yamda, Yoshiro Maru, and Toshiko Motoji
    • Organizer
      アメリカ血液学会総会
    • Place of Presentation
      米国、アトランタ
    • Related Report
      2012 Research-status Report
  • [Book] 多発性骨髄腫発生病理とmixed-lineage leukemia (MLL)タンパク2014

    • Author(s)
      今井陽一、太田瑛里
    • Publisher
      日本臨床第72巻・第6号
    • Related Report
      2013 Final Research Report
  • [Book] 症例から学ぶメディカルオンコロジー2011

    • Author(s)
      今井陽一、三橋健次郎、泉二登志子
    • Total Pages
      8
    • Publisher
      医薬ジャーナル社
    • Related Report
      2011 Research-status Report

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Published: 2011-08-05   Modified: 2019-07-29  

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