The roles of calreticulin in MPN development and normal hematopoiesis.

• Project/Area Number: 15K09480
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Kawasaki Medical School (2016-2017); University of Miyazaki (2015)
• Principal Investigator: Kitanaka Akira 川崎医科大学, 医学部, 准教授 (70343308)
• Co-Investigator(Kenkyū-buntansha): 幣 光太郎 宮崎大学, 医学部, 助教 (20468028)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); 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); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 骨髄増殖性腫瘍 / Calreticulin / シグナル伝達

Outline of Final Research Achievements

We examined the effects of calreticulin (CALR) mutations on myeloproliferative neoplasms (MPNs) development. CALR mutations activated signal transducer and activator of transcription 5 (STAT5) in 293T cells in the presence of thrombopoietin receptor (MPL). Human megakaryocytic cell lines with CALR mutations showed increased growth and acquisition of cytokine-independent growth accompanied by STAT5 phosphorylation. Transgenic mice expressing a human CALR mutation developed ET, with an increase in platelet count, but not hemoglobin level or white blood cell count, in association with an increase in bone marrow mature megakaryocytes. We conclude that the C-terminal of mutant CALR activates JAK-STAT signaling specifically downstream of MPL and may have a crucial role in CALR-induced MPNs.

Research Products

• [Journal Article] Effects of mogamulizumab in adult T-cell leukemia/lymphoma in clinical practice. (2017)
  • Author(s): Sekine M, Kubuki Y, Kameda T, Takeuchi M, Toyama T, Kawano N, Maeda K, Sato S, Ishizaki J, Kawano H, Kamiunten A, Akizuki K, Tahira Y, Shimoda H, Shide K, Hidaka T, Kitanaka A, Yamashita K, Matsuoka H, Shimoda K
  • Journal Title: European journal of haematology. Volume: 98 Issue: 5 Pages: 501-507
  • DOI: 10.1111/ejh.12863
  • Peer Reviewed / Open Access
• [Journal Article] A nationwide survey of hypoplastic myelodysplastic syndrome (a multicenter retrospective study) (2017)
  • Author(s): Kobayashi T, Nannya Y, Ichikawa M, Oritani K, Kanakura Y, Tomita A, Kiyoi H, Kobune M, Kato J, Kawabata H, Shindo M, Torimoto Y, Yonemura Y, Tohyama K, et al
  • Journal Title: American Journal of Hematology Volume: 92 Issue: 12 Pages: 1324-1332
  • DOI: 10.1002/ajh.24905
  • Peer Reviewed / Open Access
• [Journal Article] Development of a complete human IgG monoclonal antibody to transferrin receptor 1 targeted for adult T-cell leukemia/lymphoma. (2017)
  • Author(s): Shimosaki S, Nakahata S, Ichikawa T, Kitanaka A, Kameda T, Hidaka T, Kubuki Y, Kurosawa G, Zhang L, Sudo Y, Shimoda K, Morishita K.
  • Journal Title: Biochem Biophys Res Commun. Volume: 485 Issue: 1 Pages: 144-151
  • DOI: 10.1016/j.bbrc.2017.02.039
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mutant calreticulin causes essential thrombocythemia (2017)
  • Author(s): Kazuya Shimoda, Kotaro Shide and Takuro Kameda
  • Journal Title: Oncotarget Volume: 8 Issue: 51 Pages: 88251-88252
  • DOI: 10.18632/oncotarget.21292
  • Peer Reviewed / Open Access
• [Journal Article] Differences in Hematological and Clinical Features Between Essential Thrombocythemia Cases With JAK2- or CALR-Mutations. (2017)
  • Author(s): Kubuki Y, Shide K, Kameda T, Yamaji T, Sekine M, Kamiunten A, Akizuki K, Shimoda H, Tahira Y, Nakamura K, Abe H, Miike T, Iwakiri H, Tahara Y, Sueta M, Hashimoto K, Yamamoto S, Hasuike S, Hidaka T, Nagata K, Kitanaka A, Shimoda K
  • Journal Title: Annals of laboratory medicine. Volume: 37 Issue: 2 Pages: 159-161
  • DOI: 10.3343/alm.2017.37.2.159
  • Peer Reviewed / Open Access
• [Journal Article] <i>TET2</i> mutation in diffuse large B-cell lymphoma (2017)
  • Author(s): Kubuki Y, Yamaji T, Hidaka T, Kameda T, Shide K, Sekine M, Kamiunten A, Akizuki K, Shimoda H, Tahira Y, Nakamura K, Abe H, Miike T, Iwakiri H, Tahara Y, Sueta M, Yamamoto S, Hasuike S, Nagata K, Kitanaka A, Shimoda K
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 56 Issue: 3 Pages: 145-149
  • DOI: 10.3960/jslrt.56.145
  • NAID: 130005465221
  • ISSN: 1346-4280, 1880-9952
  • Peer Reviewed
• [Journal Article] Calreticulin mutant mice develop essential thrombocythemia that is ameliorated by the JAK inhibitor ruxolitinib (2016)
  • Author(s): Kotaro Shide, Takuro Kameda, Takumi Yamaji, Masaaki Sekine, Naoki Inada, Ayako Kamiunten, Keiichi Akizuki, Kenichi Nakamura, Akira Kitanaka, Arata Honda, Akira Sawaguchi, Hiroo Abe, Tadashi Miike, Hisayoshi Iwakiri, Yoshihiro Tahara, Mitsue Sueta, Satoru Hasuike, Shojiro Yamamoto, Kenji Nagata, and Kazuya Shimoda
  • Journal Title: Leukemia Volume: 31 Issue: 5 Pages: 1136-1144
  • DOI: 10.1038/leu.2016.308
  • Peer Reviewed / Open Access
• [Journal Article] Aberrant PD-L1 expression via 3’-UTR disruption in multiple cancers. (2016)
  • Author(s): K.Kataoka, (27名) N. Minato, K.Kashiwase, K. Izutsu, A. Takaori-Kondo, Y. Miyazaki, S. Takahashi, T. Shibata, H. Kawamoto, Y. Akatsuka, K. Shimoda, K. Takeuchi, T. Seya, S. Miyano, S. Ogawa.
  • Journal Title: Nature Volume: 534 Issue: 7607 Pages: 402-406
  • DOI: 10.1038/nature18294
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] All-trans retinoic acid and interferon-α increase CD38 expression on adult T-cell leukemia cells and sensitize them to T cells bearing anti-CD38 chimeric antigen receptors. (2016)
  • Author(s): Mihara K, Yoshida T, Ishida S, Takei Y, Kitanaka A, Shimoda K, Morishita K, Takihara Y, Ichinohe T.
  • Journal Title: Blood Cancer J Volume: 6 Issue: 5 Pages: e421-e421
  • DOI: 10.1038/bcj.2016.30
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Splenic irradiation provides transient palliation for symptomatic splenomegaly associated with primary myelofibrosis: a report on 14 patients. (2015)
  • Author(s): Kitanaka A, Takenaka K, Shide K, Miyamoto T, Kondo T, Ozawa K, Kurokawa M, Akashi K, Shimoda K.
  • Journal Title: Int J Hematol Volume: 103 Issue: 4 Pages: 423-428
  • DOI: 10.1007/s12185-016-1940-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Gene expression profiling of loss of TET2 and/or JAK2V617F mutant hematopoietic stem cells from mouse models of myeloproliferative neoplasms. (2015)
  • Author(s): Kameda T, Shide K, Yamaji T, Kamiunten A, Sekine M, Hidaka T, Kubuki Y, Sashida G, Aoyama K, Yoshimitsu M, Abe H, Miike T, Iwakiri H, Tahara Y, Yamamoto S, Hasuike S, Nagata K, Iwama A, Kitanaka A, Shimoda K
  • Journal Title: Genom Data. Volume: 4 Pages: 102-108
  • DOI: 10.1016/j.gdata.2015.04.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Analysis of the molecular mechanism underlying bone marrow necrosis with acute lymphoblastic leukemia. (2015)
  • Author(s): Moritake H, Obara M, Sameshima N, Asada Y, Komatsu H, Hyakuna N, Sugita K, Ishida Y, Kato M, Tanizawa A, Deguchi T, Imamura T, Kitanaka A, Shimoda K, Kamimura S, Nunoi H
  • Journal Title: Int J Hematol. Volume: 102 Issue: 3 Pages: 349-356
  • DOI: 10.1007/s12185-015-1843-8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] TET2 Mutation in Adult T-Cell Leukemia/Lymphoma (2015)
  • Author(s): Shimoda K, Shide K, Kameda T, Hidaka T, Kubuki Y, Kamiunten A, Sekine M, Akizuki K, Shimoda H, Yamaji T, Nakamura K, Abe H, Miike T, Iwakiri H, Tahara Y, Sueta M, Yamamoto S, Hasuike S, Nagata K, Kitanaka A
  • Journal Title: Journal of Clinical and Experimental Hematopathology Volume: 55 Issue: 3 Pages: 145-149
  • DOI: 10.3960/jslrt.55.145
  • NAID: 130005119614
  • ISSN: 1346-4280, 1880-9952
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] ルキソリチニブ治療中の二次性骨髄線維症（Post PV-MF）に対する同種造血細胞移植 (2018)
  • Author(s): 日高智徳、秋月渓一、田平優貴、関根雅明、上運天綾子、亀田拓郎、幣光太郎、下田晴子、久冨木庸子、下田和哉
  • Organizer: 第40回日本造血細胞移植学会総会
• [Presentation] CALR del52 変異はMPLと協調してJAK-STAT経路を活性化し、マウスにETを発症させる (2017)
  • Author(s): 幣光太郎、亀田拓郎、本田新、関根雅明、上運天綾子、秋月渓一、田平優貴、日髙智徳、久冨木庸子、北中明、下田和哉
  • Organizer: 第54回日本臨床分子医学会学術集会
• [Presentation] Murine CALR mutants Homologous to human CALR mutants activate STATs, but do not develop MPNs in vivo. (2017)
  • Author(s): Shide K, Kameda T, Sekine M, Kamiunten A, Akizuki K, Tahira Y, Shimoda H, Hidaka T, Kabuki Y, Honda A, Ikawa M, Shimoda K
  • Organizer: 第79回日本血液学会学術集会
• [Presentation] CALRdel52 mutation activates the JAK-STAT pathway in coordination with MPL, and causes ET in mice. (2016)
  • Author(s): Shide k, Kameda t, Sekine M, Kamiunten A, Akizuki K, Tahira Y, Shimoda H, Hidaka T, Kubuki Y, Honda A, Kitanaka A, Shimoda K
  • Organizer: 第78回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜（神奈川県・横浜市）
• [Presentation] Physiological Expression of Calr Mutant Increases Cell Growth and Cytokine Independency in Human Cell Lines Expressing Mpl, and Develops Essential Thrombocythemia in Mice. (2016)
  • Author(s): Shine K, Kameda T, Sekine M, Kamiunten A, Akizuki K, Tahira Y, Hidaka T, Kabuki Y, Honda A, Sawaguchi A, Kitanaka A, Shimoda K
  • Organizer: 58th ASH Annual Meeting & Exposition
  • Place of Presentation: San Diego (USA)
  • Int'l Joint Research
• [Presentation] Therapies targeting the MAPK pathway improve bone marrow (BM) fibrosis induced by JAK2V617F(JAK2VF). (2015)
  • Author(s): Kotaro Shide, Takuro Kameda, Ayako Kamiunten, Masaaki Sekine, Keiichi Akizuki, Haruko Shimoda, Tomonori Hidaka, Youko Kubuki, Akira Kitanaka, Kazuya Shimoda
  • Organizer: 第77回日本血液学会学術集会
  • Place of Presentation: 金沢市
  • Year and Date: 2015-10-16