Elucidation of molecular mechanism of cytokie receptor activation by mutant CALR

• Project/Area Number: 16K09859
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Juntendo University
• Principal Investigator: ARAKI MARITO 順天堂大学, 医学(系)研究科(研究院), 准教授 (80613843)
• Co-Investigator(Kenkyū-buntansha): 森下 総司 順天堂大学, 医学部, 助教 (10635866) ; 小松 則夫 順天堂大学, 医学部, 教授 (50186798)
• Research Collaborator: ITO akihiro
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 骨髄増殖性腫瘍 / サイトカイン受容体 / 分子シャペロン / シグナル伝達 / トロンボポエチン / JAK2 / CALR / MPL / calreticulin / thrombopoietin / Calreticulin

Outline of Final Research Achievements

By studying the mechanism for the development of myeloproliferative neoplasms (MPN) by calreticulin mutation, this study uncovered that mutant CALR preferentially interacted with MPL, induced activation of MPL like cytokine, constitutively activated its downstream molecules such as JAK2, ERK1/2, and STAT5, and thus promoted the cellular transformation.

Academic Significance and Societal Importance of the Research Achievements

本研究により、CALR変異遺伝子による骨髄増殖性腫瘍(MPN)の発症メカニズムが明らかになったことから、CALR遺伝子変異を有するMPN患者に対する有効な治療薬の開発が大いに期待される。さらに、『分子シャペロンの変異による受容体活性化が引き起こす細胞腫瘍化』という新しい腫瘍生物学の概念が明らかになったことから、他の疾患や生命現象の解明に結びつくことが大いに期待される。

Research Products

• [Int'l Joint Research] Ludwig Cancer Research(ベルギー)
• [Int'l Joint Research] CeMM(オーストリア)
• [Int'l Joint Research] INSERM(フランス)
• [Journal Article] Homomultimerization of mutant calreticulin is a prerequisite for MPL binding and activation (2018)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Skewed megakaryopoiesis in human induced pluripotent stem cell-derived haematopoietic progenitor cells harbouring calreticulin mutations (2018)
  • Author(s): Hiraku Takei, Yoko Edahiro, Shuichi Mano, Nami Masubuchi, Yoshihsa Mizukami, Misa Imai, Soji Morishita, Kyohei Misawa, Tomonori Ochiai, Satoshi Tsuneda, Hiroshi Endo, Sou Nakamura, Koji Eto, Akimichi Ohsaka, Marito Araki, Norio Komatsu
  • Journal Title: British Journal of Haematology Volume: 印刷中 Issue: 6 Pages: 791-802
  • DOI: 10.1111/bjh.15266
  • Peer Reviewed
• [Journal Article] Mutant molecular chaperone activates cytokine receptor as a homomultimer (2018)
  • Author(s): Araki Marito、Komatsu Norio
  • Journal Title: Oncotarget Volume: 9 Issue: 81 Pages: 35201-35202
  • DOI: 10.18632/oncotarget.26221
  • Peer Reviewed / Open Access
• [Journal Article] Development of myeloproliferative neoplasms by mutant calreticulin: underlying mechanisms (2018)
  • Author(s): 荒木 真理人
  • Journal Title: Rinsho Ketsueki Volume: 59 Issue: 8 Pages: 1072-1077
  • DOI: 10.11406/rinketsu.59.1072
  • NAID: 130007472202
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Mutational subtypes of JAK2 and CALR correlate with different clinical features in Japanese patients with myeloproliferative neoplasms. (2018)
  • Author(s): Misawa K, Yasuda H, Araki M, Ochiai T, Morishita S, Shirane S, Edahiro Y, Gotoh A, Ohsaka A, Komatsu N.
  • Journal Title: Int J Hematol Volume: 印刷中 Issue: 6 Pages: 673-680
  • DOI: 10.1007/s12185-018-2421-7
  • Peer Reviewed
• [Journal Article] The 2014 BCSH criteria and the 2016 WHO criteria for essential thrombocythemia: A comparison in a large-scale cohort. (2018)
  • Author(s): Ochiai T, Yasuda H, Araki M, Misawa K, Morishita S, Nudejima M, Hironaka Y, Shirane S, Edahiro Y, Gotoh A, Ohsaka A, Komatsu N.
  • Journal Title: Eur J Haematol Volume: 印刷中 Issue: 6 Pages: 544-549
  • DOI: 10.1111/ejh.13041
  • Peer Reviewed
• [Journal Article] Novel molecular mechanism of cellular transformation by a mutant molecular chaperone in myeloproliferative neoplasms (2017)
  • Author(s): Araki Marito、Komatsu Norio
  • Journal Title: Cancer Sci Volume: 108 Issue: 10 Pages: 1907-1912
  • DOI: 10.1111/cas.13327
  • Peer Reviewed / Open Access
• [Journal Article] Somatic mutations of calreticulin in myeloproliferative neoplasms (2017)
  • Author(s): Imai Misa、Araki Marito、Komatsu Norio
  • Journal Title: Int J Hematol Volume: 105 Issue: 6 Pages: 743-747
  • DOI: 10.1007/s12185-017-2246-9
  • Peer Reviewed / Open Access
• [Journal Article] The 2016 WHO diagnostic criteria for polycythemia vera renders an accurate diagnosis to a broader range of patients including masked polycythemia vera: Comparison with the 2008 WHO diagnostic criteria. (2017)
  • Author(s): Misawa K, Yasuda H, Araki M, Ochiai T, Morishita S, Nudejima M, Hironaka Y, Shirane S, Edahiro Y, Gotoh A, Ohsaka A, Komatsu N.
  • Journal Title: Am J Hematol Volume: 92 Issue: 7
  • DOI: 10.1002/ajh.24752
  • Peer Reviewed
• [Journal Article] 骨髄増殖性腫瘍におけるドライバー遺伝子変異による腫瘍化の分子メカニズム (2017)
  • Author(s): 荒木真理人
  • Journal Title: 最新醫學 Volume: 72 Pages: 1522-1528
• [Journal Article] 骨髄増殖性腫瘍を引き起こす変異型calreticulinによるTPO受容体の活性化. (2016)
  • Author(s): 今井美沙, 荒木真理人, 森下総司, 小松則夫.
  • Journal Title: 血液内科 Volume: 73 Pages: 789-793
• [Journal Article] 骨髄増殖性腫瘍の遺伝子変異 最近の知見. (2016)
  • Author(s): 荒木真理人, 森下総司, 小松則夫.
  • Journal Title: 臨床血液. Volume: 57 Pages: 2526-2534
  • Peer Reviewed
• [Presentation] The molecular mechanism of oncogenic activation of thrombopoietin receptor by mutant calreticulin (2018)
  • Author(s): Marito Araki
  • Organizer: The 1st MPN Summit
  • Int'l Joint Research / Invited
• [Presentation] Boarding on the secretary pathway is required for the oncogenic property of mutant calreticulin (2018)
  • 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 the European Hematology Association
  • Int'l Joint Research
• [Presentation] Copy number of JAK2V617F modulates human hematopoietic cell differentiation (2018)
  • Author(s): Edahiro Y, Mano S, Takei H, Morishita S, Tsuneda S, Ohsaka A, Araki M, Komatsu N.
  • Organizer: 8th International Conference on Myeloproliferative Neoplasms
  • Int'l Joint Research
• [Presentation] 変異型分子シャペロンによるサイトカイン受容体活性化の分子メカニズム (2018)
  • Author(s): 荒木真理人, 小松則夫
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 変異型CALRの多量体化はMPLとの結合と活性化に必須である (2018)
  • Author(s): 荒木真理人, 楊印杰, 今井美沙, 水上喜久, 木原慶彦, 角南義孝, 増渕菜弥, 枝廣陽子, 弘中由美, 大佐賀智, 大坂顯通, 小松則夫
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] Wild-type JAK2 may suppress mutant JAK2 activity in cytokine receptor activation. (2018)
  • Author(s): Kitazawa S, Araki M, Morishita S, Yang Y, Imai M, Ohsaka A, Komatsu N.
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] APL細胞の分化誘導におけるATRA標的遺伝子の同定. (2018)
  • Author(s): 角南義孝, 荒木真理人, 山本誠司, 堀内祥行, 辻岡一也, 薫 茂, 今井美沙, 森下総司, 大坂顯通, 小松則夫.
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] トリプルネガティブ本態性血小板血症症例の臨床像と遺伝子変異. (2018)
  • Author(s): 稲野資明, 荒木真理人, 福田泰隆, 森下総司, 落合友則, 三澤恭平, 伊藤雅文, 山本紘司, 楊印杰, 田口鉄平, 枝廣陽子, 今井美沙, 後藤明彦, 大坂顯通, 小松則夫.
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] 細胞減少療法はPMF患者における腎機能の悪化を防止する. (2018)
  • Author(s): 福田泰隆, 荒木真理人, 山本紘司, 森下総司, 稲野資明, 三澤恭平, 落合友則, 枝廣陽子, 今井美沙, 後藤明彦, 大坂顯通, 小松則夫.
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] Introduction of CALR and JAK2 V617F mutations to UT-7/Epo and K562 by the CRISPR/Cas9 system. (2018)
  • Author(s): Yasuda S, Aoyama S, Watanabe D, Araki M, Komatsu N, Miura O, Kawamata N.
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] JAK2V617F変異アレル数はヒト血球分化を変化させる. (2018)
  • Author(s): 竹井拓, 枝廣陽子, 李麗華, 水上喜久, 森下総司, 大坂顯通, 荒木真理人, 小松則夫.
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] 骨髄線維化を伴う骨髄異形成症候群の臨床病態および分子発症機序の解明. (2018)
  • Author(s): 新谷直樹, 原田浩徳, 原田結花, 飯塚弘子, 森下総司, 荒木真理人, 大坂顯通, 土岐典子, 大橋一輝, 萩原政夫, 小松則夫.
  • Organizer: 第80回日本血液学会学術集会
• [Presentation] The Zygosity of JAK2V617F Determines the Disease Entities of Myeloproliferative Neoplasms By Modulating Erythropoiesis but Not Megakaryopoiesis (2018)
  • Author(s): Takei H, Edahiro Y, Li L, Mizukami Y, Imai M, Morishita S, Ohsaka A, Araki M, Komatsu N.
  • Organizer: 60th Annual Meeting & Exposition of American Society of Hematology
  • Int'l Joint Research
• [Presentation] Secreted Mutant Calreticulins As Rogue Cytokines Trigger Thrombopoietin Receptor Activation Specifically in CALR Mutated Cells: Perspectives for MPN Therapy (2018)
  • Author(s): Pecquet C, Araki M, et al.
  • Organizer: 60th Annual Meeting & Exposition of American Society of Hematology
  • Int'l Joint Research
• [Presentation] SLAMF7high CD16negative Monocytes Increase in Peripheral Blood of Patients with Myelofibrosis in Correlation with JAK2V617F Mutation (2018)
  • Author(s): Maekawa T, Kato S, Okada Y, Tachi N, Teramoto M, Kawamura T, Osawa Y, Kobayashi S, Sato K, Hashimoto M, Suzu S, Usuki K, Morishita S, Araki M, Komatsu N, Kimura F.
  • Organizer: 60th Annual Meeting & Exposition of American Society of Hematology
  • Int'l Joint Research
• [Presentation] The molecular mechanism of oncogenic activation of thrombopoietin receptor by mutant calreticulin (2018)
  • Author(s): Marito Araki
  • Organizer: The 3rd MPN Conference in Asia
  • Int'l Joint Research / Invited
• [Presentation] Activation of the Thrombopoietin Receptor by Mutant Calreticulin in CALR-Mutant Myeloproliferative Neoplasms. (2017)
  • Author(s): Araki M
  • Organizer: The Gordon Research Conference on Cell Biology of Megakaryocytes & Platelets.
  • Place of Presentation: Lucca, Italy
  • Year and Date: 2017-02-26
  • Int'l Joint Research / Invited
• [Presentation] Skewed megakaryopoiesis by mutant calreticulin is associated with increased GATA2 expression (2017)
  • Author(s): Hiraku Takei, Shuichi Mano, Nami Masubuchi, Yoshihisa Mizukami, Misa Imai, Soji Morishita, Yoko Edahiro Yumi Hironaka Mai Nudejima Hiroshi Endo, Sou Nakamura, Koji Eto, Akimichi Ohsaka, Marito Araki, Norio Komatsu
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] 骨髄増殖性腫瘍に見出される変異型 CALR 蛋白質の細胞内局在 (2017)
  • Author(s): 林英里奈, 荒木真理人, 増渕菜弥, 水上喜久, 楊印杰, 今井美沙 , 弘中由美, 竹井拓, 木原慶彦, 枝廣陽子, 大坂顯通, 小松則夫
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Engagement of mutant calreticulin and MPL in a cellular compartment is required for MPL activation (2017)
  • Author(s): Nami Masubuchi, Marito Araki, Erina Hayashi, Yinjie Yang, Misa Imai Yoshihisa Mizukami, Yumi Hironaka, Hiraku Takei, Soji Morishita, Yoshihiko Kihara, Yoko Edahiro, Akimichi Ohsaka, Norio Komatsu
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Mechanisms governing the accumulation of mutant calreticulin (2017)
  • Author(s): Yoshihiko Kihara, Marito Araki, Yinjie Yang, Misa Imai, Nami Masubuchi, Yoshihisa Mizukami, Yumi Hironaka, Hiraku Takei, Yoko Edahiro, Akimichi Ohsaka, Norio Komatsu
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] Localization of mutant calreticulin in the Golgi apparatus is required for its oncogenic capacity (2017)
  • Author(s): Nami Masubuchi, Marito Araki, Erina Hayashi, Yinjie Yang, Misa Imai Yoshihiko Kihara, Yoshihisa Mizukami, Yumi Hironaka, Hiraku Takei, Yoko Edahiro, Akimichi Ohsaka, Norio Komatsu
  • Organizer: 59th Annual Meeting & Exposition of American Society of Hematology
  • Int'l Joint Research
• [Presentation] Establishment of an in vitro model for the skewed megakaryopoiesis by calreticulin mutation in human cells (2017)
  • Author(s): Hiraku Takei, Shuichi Mano, Nami Masubuchi, Yoshihisa Mizukami, Soji Morishita, Misa Imai, Yoko Edahiro, Yumi Hironaka, Mai Nudejima, Satoshi Tsuneda, Hiroshi Endo, Sou Nakamura, Koji Eto, Akimichi Ohsaka, Marito Araki, Norio Komatsu
  • Organizer: 22nd Congress of the European Hematology Association
  • Int'l Joint Research
• [Presentation] 変異型CALRの細胞内コンパートメントへの局在がトロンボポエチン受容体の活性化に必要である (2017)
  • Author(s): 荒木真理人, 小松則夫
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] The mechanism of the development of myeloproliferative neoplasms by mutant molecular chaperone (2017)
  • Author(s): Marito Araki
  • Organizer: The 26th KOGO Annual Conference 2017
  • Int'l Joint Research / Invited
• [Presentation] The mechanism of the development of myeloproliferative neoplasms by mutant molecular chaperone (2017)
  • Author(s): Marito Araki
  • Organizer: 第79回日本血液学会学術集会シンポジウム「骨髄系腫瘍とクリニカルシーケンス」
  • Invited
• [Presentation] A novel molecular mechanism of cellular transformation via a mutant molecular chaperone (2017)
  • Author(s): Marito Araki
  • Organizer: MD Anderson Cancer Center - Tokyo Oncology Consortium Sister Institute Memorial Symposium
  • Invited
• [Presentation] Mutant Calreticulin activates the thrombopoietin receptor in myeloproliferative neoplasms. (2017)
  • Author(s): Marito Araki, Yinjie Yang, Nami Masubuchi, Yoshihisa Mizukami, Misa Imai, Erina Hayashi, Yumi Hironaka, Soji Morishita, Yoko Edahiro, Akimichi Ohsaka, Norio Komatsu
  • Organizer: The annual GAP Conference
  • Int'l Joint Research
• [Presentation] 骨髄増殖生腫瘍を引き起こす変異型Calreticulinの細胞内局在 (2016)
  • Author(s): 増渕 菜弥, 荒木 真理人, Yinjie Yang, 弘中 由美, 竹井 拓, 森下 総司, 今井 美沙, 水上 喜久, Kan Shin、大坂 顯通, 小松 則夫.
  • Organizer: 第39回日本分子生物学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-11-30
• [Presentation] Mutant Calreticulin activates the thrombopoietin receptor in myeloproliferative neoplasms. (2016)
  • Author(s): Araki M, Yang Y, Masubuchi N, Hironaka Y, Takei H, Morishita S, Mizukami Y, Kan S, Shirane S, Edahiro Y, Sunami Y, Ohsaka A, Komatsu N.
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] Modeling MPN phenotypes in vitro by using iPSC harboring CALR ins5 mutation. (2016)
  • Author(s): Takei H, Masubuchi N, Mano S, Araki M, Morishita S, Mizukami Y, Kan S, Edahiro Y, Sunami Y, Hironaka Y, Endo H, Nakamura S, Eto K, Ohsaka A, Komatsu N.
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] Cell surface localization of mutant Calreticulin that induces myeloproliferative neoplasms (MPNs). (2016)
  • Author(s): Masubuchi N, Araki M, Yang Y, Hironaka Y, Takei H, Morishita S, Mizukami Y, Kan S, Ohsaka A, Komatsu N.
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-13
• [Presentation] Mutant Calreticulin activates JAK2 by an interaction with thrombopoietin receptor in myeloproliferative neoplasm cells. (2016)
  • Author(s): Araki M, Komatsu N.
  • Organizer: 第75回日本癌学会学術総会.
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Activation of the thrombopoietin receptor by mutant calreticulin in CALR-mutant myeloproliferative neoplasms. (2016)
  • Author(s): Araki M, Yang Y, Masubuchi N, Hironaka Y, Takei H, Morishita S, Mizukami Y, Kan S, Shirane S, Edahiro Y, Sunami Y, Ohsaka A, Komatsu N.
  • Organizer: 21st Congress of the European Hematology Association.
  • Place of Presentation: Copenhagen, Denmark
  • Year and Date: 2016-06-09
  • Int'l Joint Research
• [Remarks] 研究室ホームページ
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/ketsueki_naika/
• [Remarks] 研究室ホームページ
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/ketsueki_naika/k4.html
• [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
  • Industrial Property Number: 2019-036119
  • Filing Date: 2019