Elucidation of the molecular pathogenesis of myeloproliferative neoplasms with CALR mutations for the development of novel therapeutic strategies.
| Project/Area Number |
19K07880
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 52010:General internal medicine-related
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| Research Institution | Kawasaki Medical School |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
通山 薫 川崎医科大学, 医学部, 教授 (80227561)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 骨髄増殖性腫瘍 / calreticulin / チロシンキナーゼ / Calreticulin / MPL |
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| Outline of Research at the Start |
骨髄増殖性腫瘍（MPN）は、サイトカイン受容体シグナル伝達系の恒常的な活性化を引き起こす遺伝子変異によって発症する。近年、JAK2に次いでMPN症例に変異が多い遺伝子としてCALRが見いだされたが、その発症メカニズムについては不明な点が多い。本研究では、変異CALRのタンパク合成から輸送、MPLとの結合までを含んだいずれかの過程を阻害する化合物を見いだすことによって、MPNの病態形成に重要な分子を抽出し、得られた知見をもとに新たな治療法の開発を目指す。
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| Outline of Final Research Achievements |
In this study, we attempted to identify key molecules in the intracellular signaling mechanism by which mutant CALR activates MPL-mediated signaling. We found that the Src-selective inhibitor PP2 and the Bcr-Abl/Src inhibitor bosutinib suppressed the proliferation of F-36P-MPL cells expressing CALR mutant and decreased the transcriptional activity of STAT5, which was enhanced by the expression of mutated CALR, in 293T cells. Of note, bosutinib inhibited cell proliferation at clinically achievable concentrations. Specific supression of Lyn, a major Src family member in hematopoietic cells, inhibited mutant CALR-dependent cell proliferation, indicating that Lyn may play an important role in the signaling mechanism by mutant CALR.
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| Academic Significance and Societal Importance of the Research Achievements |
近年、骨髄増殖性腫瘍（MPN）の病態解明が著しく進歩し、病因となる変異遺伝子産物を標的とした新規薬剤JAK阻害薬が臨床応用されている。JAK阻害薬はMPN症例の多くに変異が認められるJAK2を標的としており、臨床症状の改善に有効であるが、血球減少の副作用がある。疾患の発症・進展に関与する変異型JAK2と、正常な造血の維持に必要な野生型JAK2の間で酵素活性を有する部分の構造に差異はなく、両者に異なった作用を示す阻害薬の開発は極めて困難である。本研究で見出した変異CALR下流分子の詳細を解明することは、これまでと異なった作用機序のMPN治療薬開発につながる可能性がある。
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Report
(4 results)
Research Products
(20 results)
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[Journal Article] Prognosis of Indolent Adult T-Cell Leukemia/Lymphoma2022
Author(s)
Kameda T, Shide K, Tahira Y, Sekine M, Sato S, Ishizaki J, Takeuchi M, Akizuki K, Kamiunten A, Shimoda H, Toyama T, Maeda K, Yamashita K, Kawano N, Kawano H, Hidaka T, Yamaguchi H, Kubuki Y, Kitanaka A, Matsuoka H, Shimoda K
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Journal Title
Viruses
Volume: 14
Issue: 4
Pages: 710-710
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Whole-genome landscape of adult T-cell leukemia/lymphoma2022
Author(s)
Kogure Y, Kameda T, Koya J, Yoshimitsu M, Nosaka K, Yasunaga JI, Imaizumi Y, Watanabe M, Saito Y, Okada A, Kakiuchi N, Nannya Y,Kitanaka A, Hidaka M, Nakano N, Utsunomiya A, Sica RA, Acuna-Villaorduna A, Janakiram M, Shah U, Shibata T, Takeuchi K, Ogawa S, Ye BH, Shimoda K, Kataoka K（他20名、26番目）
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Journal Title
Blood
Volume: 139
Issue: 7
Pages: 967-982
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Single-Cell Analysis of the Multicellular Ecosystem in Viral Carcinogenesis by HTLV-12021
Author(s)
Koya J, Saito Y, Kameda T, Kogure Y, Yuasa M, Nagasaki J, McClure MB, Shingaki S, Tabata M, Tahira Y, Akizuki K, Kamiunten A, Sekine M, Shide K, Kubuki Y, Hidaka T, Kitanaka A, Nakano N, Utsunomiya A, Togashi Y, Ogawa S, Shimoda K, Kataoka K
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Journal Title
Blood Cancer Discovery
Volume: 2
Issue: 5
Pages: 450-467
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Association between microRNA-527 and glypican-3 in hepatocellular carcinoma2021
Author(s)
Nomura K, Kitanaka A, Iwama H, Tani J, Nomura T, Nakahara M, Ohura K, Tadokoro T, Fujita K, Mimura S, Yoneyama H, Kobara H, Morishita A, Okano K, Suzuki Y, Tsutsi K, Himoto T, Masaki T
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Journal Title
Oncology Letters
Volume: 21
Issue: 3
Pages: 229-229
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Higher average chemotherapy dose intensity improves prognosis in patients with aggressive adult T‐cell leukemia/lymphoma2020
Author(s)
Sekine M, Kameda T, Shide K, Maeda K, Toyama T, Kawano N, Takeuchi M, Kawano H, Sato S, Ishizaki J, Kukita T, Kamiunten A, Akizuki K, Tahira Y, Shimoda H, Hidaka T, Yamashita K, Matsuoka H, Kitanaka A, Kubuki Y, Shimoda K
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Journal Title
European Journal of Haematology
Volume: 106
Issue: 3
Pages: 398-407
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Clinical significance of soluble CADM1 as a novel marker for adult T-cell leukemia/lymphoma2020
Author(s)
Nakahata S, Syahrul C, Nakatake A, Sakamoto K, Yoshihama M, Nishikata I, Ukai Y, Matsuura T, Kameda T, Shide K, Kubuki Y, Hidaka T, Kitanaka A, Ito A, Takemoto S, Nakano N, Saito M, Iwanaga M, Sagara Y, Mochida K, Amano M, Maeda K, Sueoka E, Okayama A, Utsunomiya A, Shimoda K, Watanabe T, Morishita K
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Journal Title
Haematologica
Volume: 106
Pages: 532-542
Related Report
Peer Reviewed
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[Journal Article] Binimetinib, a novel MEK1/2 inhibitor, exerts anti-leukemic effects under inactive status of PI3Kinase/Akt pathway.2019
Author(s)
Sakakibara K, Tsujioka T, Kida JI, Kurozumi N, Nakahara T, Suemori SI, Kitanaka A, Arao Y, Tohyama K
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Journal Title
International journal of hematology
Volume: 110
Issue: 2
Pages: 213-227
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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