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Mechanisms governing intracellular accumulation of mutant CALR proteins

Research Project

Project/Area Number 18K16127
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 54010:Hematology and medical oncology-related
Research InstitutionJuntendo University

Principal Investigator

Yoshihiko Kihara  順天堂大学, 医学部, 博士研究員 (70812999)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Keywords造血器腫瘍 / 骨髄増殖性腫瘍 / calreticulin / 細胞内蓄積 / 蛋白質分解経路 / 蛋白質分泌経路 / 蛋白質の切断 / 抗体医療 / 抗体医薬
Outline of Final Research Achievements

In this study, we aimed to elucidate the regulatory mechanism of intracellular accumulation of mutant CALR proteins that causes myeloproliferative neoplasms (MPNs). As a result, it was found that the majority of mutant CALR proteins exist as low molecular weight forms that could not be detected by existing antibodies. Antibodies against the low-molecular-weight mutant CALR protein that was thought to be cleaved by a protease(s) were generated. The antibodies bound strongly to both the full-length and low-molecular-weight mutant CALR proteins. Chimeric antibodies and bispecific antibodies based on the antibodies exhibited their potential as therapeutic agents for MPN patients with CALR mutations.

Academic Significance and Societal Importance of the Research Achievements

本研究により、世界に先駆けて、骨髄増殖性腫瘍(MPN)の発症原因分子である変異型CALR蛋白質の細胞内蓄積制御メカニズムが明らかになった。さらに、既存の抗体では検出されない低分子量の変異型CALR蛋白質の捕捉を可能とする抗体も開発できた。そして、この抗体がCALR遺伝子変異を有するMPN患者に対する治療薬として有望であることが示された。これらの研究成果は、CALR遺伝子変異によるMPN発症メカニズムを明らかにしただけでなく、変異型CALR蛋白質を標的とする新規治療戦略の開発の道筋を提示しており、学術的にも社会的にも意義深いと言える。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (18 results)

All 2020 2019 2018

All Journal Article (3 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 3 results,  Open Access: 2 results) Presentation (12 results) (of which Int'l Joint Research: 4 results) Patent(Industrial Property Rights) (3 results) (of which Overseas: 1 results)

  • [Journal Article] Mutant calreticulin interacts with MPL in the secretion pathway for activation on the cell surface2019

    • Author(s)
      Masubuchi Nami、Araki Marito、Yang Yinjie、Hayashi Erina、Imai Misa、Edahiro Yoko、Hironaka Yumi、Mizukami Yoshihisa、Kihara Yoshihiko、Takei Hiraku、Nudejima Mai、Koike Masato、Ohsaka Akimichi、Komatsu Norio
    • Journal Title

      Leukemia

      Volume: 34 Issue: 2 Pages: 499-509

    • DOI

      10.1038/s41375-019-0564-z

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Hlf marks the developmental pathway for hematopoietic stem cells but not for erythro-myeloid progenitors.,2019

    • Author(s)
      Tomomasa Yokomizo, Naoki Watanabe, Terumasa Umemoto, Junichi Matsuo, Ryota Harai, Yoshihiko Kihara, Eri Nakamura, Norihiro Tada, Tomohiko Sato, Tomoiku Takaku, Akihiko Shimono, Hitoshi Takizawa, Naomi Nakagata, Seiichi Mori, Mineo Kurokawa, Daniel Tenen, Motomi Osato, Toshio Suda, and Norio Komatsu.
    • Journal Title

      J Exp Med

      Volume: 216 Issue: 7 Pages: 1599-1614

    • DOI

      10.1084/jem.20181399

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Homomultimerization of mutant calreticulin is a prerequisite for MPL binding and activation2018

    • Author(s)
      Araki Marito、Yang Yinjie、Imai Misa、Mizukami Yoshihisa、Kihara Yoshihiko、Sunami Yoshitaka、Masubuchi Nami、Edahiro Yoko、Hironaka Yumi、Osaga Satoshi、Ohsaka Akimichi、Komatsu Norio
    • Journal Title

      Leukemia

      Volume: 33 Issue: 1 Pages: 122-131

    • DOI

      10.1038/s41375-018-0181-2

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Therapeutic potential of myeloproliferative neoplasms by antibody targeting mutant calreticulin2020

    • Author(s)
      Yoshihiko Kihara, Marito Araki, Misa Imai, Yasutaka Fukuda, Yosuke Mori, Teppei Taguchi, Nami Masubuchi, Yo Mabuchi, Yinjie Yang, Yoshihisa Mizukami, Soji Morishita, Chihiro Akazawa, Akimichi Ohsaka, Norio Komatsu
    • Organizer
      第82回日本血液学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Therapeutic potential of an antibody targeting the cleaved form of mutant calreticulin in myeloproliferative neoplasms2020

    • Author(s)
      Yoshihiko Kihara, Marito Araki, Misa Imai, Yosuke Mori, Mei Horino, Satoko Ogata, Syunpei Yoshikawa, Teppei Taguchi, Nami Masubuchi, Yo Mabuchi, Yinjie Yang, Yasutaka Fukuda, Soji Morishita, Takehiro Suzuki, Naoshi Domae, Motoyuki Shimonaka, Chihiro Akazawa, Akimichi Ohsaka, Norio Komatsu
    • Organizer
      62nd ASH Annual Meeting
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 典型的なドライバー遺伝子変異の見いだされない本態性血小板血症の特徴2020

    • Author(s)
      荒木真理人, 稲野資明, 森下総司, 木原慶彦, 奥田真帆, 楊印杰, 今井美沙, 枝廣陽子, 伊藤雅文, 大佐賀智, 落合友則, 三澤恭平, 大坂顯通, 小松則夫
    • Organizer
      第30回日本サイトメトリー学会学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] Concomitant occurrence of polyclonal hematopoiesis and cell-autonomous megakaryopoiesis in triple-negative essential thrombocythemia2020

    • Author(s)
      Inano T, Araki M, Morishita S, Imai M, Kihara Y, Okuda M, Ito M, Osaga S, Yang Y, Edahiro Y, Ochiai T, Misawa K, Fukuda Y, Ohsaka A, Komatsu N
    • Organizer
      62nd Annual Meeting & Exposition of American Society of Hematology
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 抗TfR1抗体による真性多血症内因性赤芽球コロニーの形成阻害2019

    • Author(s)
      木原 慶彦,増渕 菜弥,張 黎臨,荒木 真理人,小松 則夫
    • Organizer
      第81回日本血液学会学術集会,東京
    • Related Report
      2019 Research-status Report
  • [Presentation] 変異型calreticulin特異的配列によるゴルジ体への局在2019

    • Author(s)
      水上 喜久,荒木 真理人,今井 美沙,林 英里奈,増渕 菜弥,楊 印杰,木原 慶彦,弘中 由美,大坂 顯通,小松 則夫
    • Organizer
      第81回日本血液学会学術集会,東京
    • Related Report
      2019 Research-status Report
  • [Presentation] 変異型CALRはMPLと分泌経路で相互作用し細胞表面で活性化を引き起こす2019

    • Author(s)
      増渕 菜弥,荒木 真理人,楊 印杰,林 英里奈,今井 美沙,枝廣 陽子,弘中 由美,水上 喜久,木原 慶彦,小池 正人,大坂 顯通,小松 則夫
    • Organizer
      第81回日本血液学会学術集会,東京
    • Related Report
      2019 Research-status Report
  • [Presentation] 変異型特異的配列による変異型CALRの細胞内局在の規定2019

    • Author(s)
      水上 喜久,荒木 真理人,今井 美沙,林 英里奈,増渕 菜弥,楊 印杰,木原 慶彦,弘中 由美,大坂 顯通,小松 則夫
    • Organizer
      第29回日本サイトメトリー学会学術集会,東京
    • Related Report
      2019 Research-status Report
  • [Presentation] 分泌経路における変異型分子シャペロンとサイトカイン受容体の会合による細胞の腫瘍化2019

    • Author(s)
      増渕 菜弥,荒木 真理人,木原 慶彦,楊 印杰,今井 美沙,水上 喜久,林 英里奈,弘中 由美,竹井 拓,枝廣 陽子,大坂 顯通,小松 則夫
    • Organizer
      第29回日本サイトメトリー学会学術集会,東京
    • Related Report
      2019 Research-status Report
  • [Presentation] calreticulin変異による骨髄増殖性腫瘍発症の分子メカニズム2019

    • Author(s)
      荒木 真理人,楊 印杰,増渕 菜弥,林 英里奈,水上 喜久,木原 慶彦,今井 美沙,弘中 由美,橳島 麻衣,枝廣 陽子,大坂 顯通,小松 則夫
    • Organizer
      第29回日本サイトメトリー学会学術集会,東京
    • Related Report
      2019 Research-status Report
  • [Presentation] Boarding on the secretary pathway is required for the oncogenic property of mutant calreticulin2018

    • Author(s)
      Araki M, Masubuchi N, Hayashi E, Yang Y, Imai M, Kihara Y, Mizukami Y, Hironaka Y, Edahiro Y, Ohsaka A, Komatsu N
    • Organizer
      23rd Congress of European Hematology Association, Stockholm, Sweden
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Secreted Mutant Calreticulins As Rogue Cytokines Trigger Thrombopoietin Receptor Activation Specifically in CALR Mutated Cells: Perspectives for MPN Therapy2018

    • Author(s)
      C Pecquet, T Balligand, I Chachoua, A Roy, G Vertenoeil, D Colau, E Fertig, C Marty, H Nivarthi, JP Defour, E Xu, E Hug, H Gisslinger, B Gisslinger, M Schalling, I Carola Casetti, E Rumi, D Pietra, C Cavalloni, L Arcaini, M Cazzola, N Komatsu, Y Kihara, et. al.
    • Organizer
      60th ASH Annual Meeting, San Diego, USA
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Patent(Industrial Property Rights)] 抗切断型変異CALR-CD3二重特異性抗体及び医薬組成物2020

    • Inventor(s)
      小松則夫、荒木真理人、木原慶彦ら、計7名
    • Industrial Property Rights Holder
      順天堂大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report
  • [Patent(Industrial Property Rights)] 切断型の変異型Calreticulinに結合する抗体、及び骨髄増殖性腫瘍の診断、予防又は治療薬2020

    • Inventor(s)
      荒木真理人、小松則夫、木原慶彦
    • Industrial Property Rights Holder
      順天堂大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2019 Research-status Report
    • Overseas
  • [Patent(Industrial Property Rights)] 非公開2019

    • Inventor(s)
      荒木真理人、小松則夫、木原慶彦
    • Industrial Property Rights Holder
      荒木真理人、小松則夫、木原慶彦
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2025-01-30  

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