Myeloproliferative neoplasms research for drug discovery focusing on CALR mutation and fibrocyte
| Project/Area Number |
17H04210
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | University of Miyazaki |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
久冨木 庸子 宮崎大学, 医学部, 講師 (00284836)
幣 光太郎 宮崎大学, 医学部, 助教 (20468028)
日高 智徳 宮崎大学, 医学部, 講師 (40381115)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2019: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2018: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2017: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000)
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| Keywords | 骨髄線維症 / fibrocyte / シグナル伝達 / 骨髄増殖性腫瘍 / 癌 |
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| Outline of Final Research Achievements |
Elucidation of the pathophysiology of myeloproliferative neoplasms (MPNs) has been greatly advanced by the identification of the driver mutations JAK2 and CALR. On the other hand, the mechanism by which CALR mutations cause MPN and the mechanism of fibrosis, which is the most important feature of myelofibrosis, remain unclear.
We elucidated the role of CALR in normal hematopoiesis and the mechanism of clonal expansion of CALR-mutated aberrant hematopoietic stem cells. We also found that the majority of collagen-producing cells in the bone marrow, which are the main players in fibrosis, are neoplastic fibrocytes that differentiate from tumor clones via monocytes.
These are major achievements that promote the understanding of the pathogenesis of MPN, leading to the development of new treatment methods that meet unmet needs of patients.
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| Academic Significance and Societal Importance of the Research Achievements |
骨髄増殖性腫瘍(MPN)の有病率は血液腫瘍性疾患の中でも高く、患者は慢性的な随伴症状や重症化した病態である骨髄線維症への進展に苦しんでいる。本研究により、MPNの主要なドライバー変異であるCALR変異がMPNを発症させる機序について、未解明の疑問に答える大きな知見を示すことができた。また、骨髄線維化の本態であるコラーゲン産生細胞のほとんどが、腫瘍性単球由来のfibrocyteであるという従来の定説を覆す知見も示すことができた。これらの成果は、学術的には病態解明の歩みに大きな一歩を刻むものであり、社会的にはアンメットニーズに応えMPNの発症・進展を食い止める革新的治療開発の礎となる成果である。
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Report
(4 results)
Research Products
(47 results)
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[Journal Article] Effect of ruxolitinib therapy on the quality of life of Japanese patients with myelofibrosis.2018
Author(s)
Oritani K, Ohishi K, Okamoto S, Kirito K, Komatsu N, Tauchi T, Handa H, Saito S, Takenaka K, Shimoda K, Okada H, Amagasaki T, Wakase S, Shimozuma K, Akashi K
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Journal Title
Curr Med Res Opin
Volume: 34
Issue: 3
Pages: 531-537
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Thrombohemorrhagic events, disease progression, and survival in polycythemia vera and essential thrombocythemia: a retrospective survey in Miyazaki prefecture, Japan2018
Author(s)
Kamiunten A, Shide K, Kameda T, Sekine M, Kubuki Y, Ito M, Toyama T, Kawano N, Marutsuka K, Maeda K, Takeuchi M, Kawano H, Sato S, Ishizaki J, Akizuki K, Tahira Y, Shimoda H, Hidaka T, Yamashita K, Matsuoka H, Shimoda K.
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Journal Title
Int J Hematol
Volume: 印刷中
Issue: 6
Pages: 681-688
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Early/prefibrotic primary myelofibrosis in patients who were initially diagnosed with essential thrombocythemia2018
Author(s)
Kamiunten A, Shide K, Kameda T, Ito M, Sekine M, Kubuki Y, Hidaka T, Akizuki K, Tahira Y, Toyama T, Kawano N, Marutsuka K, Maeda K, Takeuchi M, Kawano H, Sato S, Ishizaki J, Shimoda H, Yamashita K, Matsuoka H, Shimoda K:
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Journal Title
International Journal of Hematology
Volume: 108
Issue: 4
Pages: 411-415
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Evaluation of the dose and efficacy of ruxolitinib in Japanese patients with myelofibrosis.2018
Author(s)
Kirito K, Okamoto S, Ohishi K, Tauchi T, Handa H, Saito S, Takenaka K, Shimoda K, Oritani K, Akashi K, Okada H, Amagasaki T, Suzuki K, Yonezu T, Komatsu N
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Journal Title
Int J Hematol
Volume: 107(1)
Issue: 1
Pages: 92-97
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Impact of TET2 deficiency on iron metabolism in erythroblasts.2017
Author(s)
Inokura K, Fujiwara T, Saito K, Iino T, Hatta S, Okitsu Y, Fukuhara N, Onishi Y, Ishizawa K, Shimoda K, Harigae H
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Journal Title
Exp Hematol.
Volume: -
Pages: 56-67
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Hmga2 collaborates with JAK2 V617F in the development of myeloproliferative neoplasms2017
Author(s)
Ueda K, Ikeda K, Ikezoe T, Harada-Shirado K, Ogawa K, Hashimoto Y, Sano T, Ohkawara H, Kimura S, Shichishima-Nakamura A, Nakamura Y, Shikama Y, Mori T, Mason PJ, Bessler M, Morishita S, Komatsu N, Shide K, Shimoda K, Koide S, Aoyama K, Oshima M, Iwama Aand Takeishi Y.
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Journal Title
Blood Advances
Volume: 1
Issue: 15
Pages: 1001-1015
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Loss of Tyrosine Kinase 2 Does Not Affect the Severity of Jak2V617F-induced Murine Myeloproliferative Neoplasm.2017
Author(s)
Yamaji T, Shide K, Kameda T, Sekine M, Kamiunten A, Hidaka T, Kubuki Y, Shimoda H, Abe H, Miike T, Iwakiri H, Tahara Y, Sueta M, Yamamoto S, Hasuike S, Nagata K, Shimoda K
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Journal Title
Anticancer research
Volume: 37
Pages: 3841-3847
Related Report
Peer Reviewed
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[Presentation] Effects of calreticulin deficiency on hematopoietic system.2019
Author(s)
Kotaro Shide, Takuro Kameda, Ayako Kamiunten, Yoshinori Ozono, Masaya Ono, Takako Yokomizo, Sho Kubota, Yuki Tahira, Keiichi Akizuki, Masaaki Sekine, Yoko Kubuki, Tomonori Hidaka, Goro Sashida, Masahito Ikawa, Kazuya Shimoda:
Organizer
第81回日本血液学会学術集会
Related Report
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[Presentation] Transformation to acute leukemia in myeloproliferative neoplasms with IDH mutations.2019
Author(s)
Kawano M, Shide K, Kamiunten A, Kubuki Y, Takeuchi M, Matsue K, Kawano N, Yamashita K, Imataki O, Kadowaki N, Fukushima K, Karasuno T, Shimomura T, Suzushima H, Yonezawa A, Otsuka E, Saburi Y, Hidaka T, Kameda T, Akizuki K, Sekine M, Tahira Y, Shimoda K
Organizer
第81回日本血液学会学術集会
Related Report
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[Presentation] Depletion of Neoplastic CD11b zposutive Cells in Jak2V617F Mutant Mice Reduced Fibrocytes in Bone Marrow and Improved Myelofibrosis2019
Author(s)
Yoshinori Ozono:Kotaro Shide, Takuro Kameda, Ayako Kamiunten, Yuki Tahira, Masaaki Sekine, Keiichi Akizuki, Kenichi Nakamura, Hisayoshi Iwakiri, Tomonori Hidaka, Yoko Kubuki, Satoru Hasuike, Fumiyo Toyoshima, Akira Sawaguchi, Kenji Nagata, and Kazuya Shimoda:
Organizer
61th ASH Annual Meeting and Exposition
Related Report
Int'l Joint Research
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[Presentation] A retrospective analysis of treatment for patients with newly diagnosed chronic myeloid leukemia.2018
Author(s)
Yoko Kubuki, Masaaki Sekine, Ayako Kamiunten, Takanori Toyama, Masanori Takeuchi, Noriaki Kawano, Kouichi Maeda, Seiichi Satou, Junzo Ishizaki, Yuki Tahira, Keiichi Akizuki, Takuro Kameda, Kotaro Shide, Haruko Shimoda, Hiroshi Kawano, Kiyoshi Yamashita, Hitoshi Matsuoka, Tomonori Hidaka, Kazuya Shimoda:
Organizer
第80回日本血液学会学術集会
Related Report
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[Presentation] Clinical features of essential thrombocythemia in Miyazaki.2018
Author(s)
Ayako Kamiunten, Yuki Tahira, Keiichi Akizuki, Masaaki Sekine, Takuro Kameda, Kotaro Shide, Tomonori Hidaka, Yoko Kubuki, Kiyoshi Yamashita, Takanori Toyama, Kouichi Maeda, Hiroshi Kawano, Masanori Takeuchi, Hitoshi Matsuoka, Junzo Ishizaki, Kazuya Shimoda:
Organizer
第80回日本血液学会学術集会
Related Report
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[Presentation] Haploinsufficiency of Calr Confers Hematopoietic Stem Cells (HSCs) with a Clonal Advantage over Wild-Type Cells, and, in Setting of Myeloproliferative Neoplasms, Compensates for the Functions of HSCs Impaired By the Calr Mutation.2018
Author(s)
Kotaro Shide, Takuro Kameda, Ayako Kamiunten, Masaaki Sekine, Yoshinori Ozono, Takako Yokomizo, Keiichi Akizuki, Yuki Tahira, Yoko Kubuki, Tomonori Hidaka, Goro Sashida, Kazuya Shimoda:
Organizer
60th ASH Annual Meeting and Exposition.
Related Report
Int'l Joint Research
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[Presentation] Murine CALR mutants Homologous to human CALR mutants activate STATs, but do not develop MPNs in vivo.2017
Author(s)
Kotaro Shide, Takuro Kameda, Masaaki Sekine, Ayako Kamiunten, Keiichi Akizuki, Yuki Tahira, Haruko Shimoda, Tomonori Hidaka, Yoko Kubuki, Arata Honda, Masahito Ikawa, Kazuya Shimoda
Organizer
第79回日本血液学会学術集会
Related Report
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