Molecular pathogenesis and molecular therapy in RUNX1-EVI1-type leukemia.
Project/Area Number |
19K08822
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Research Category |
Grant-in-Aid for Scientific Research (C)
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Allocation Type | Multi-year Fund |
Section | 一般 |
Review Section |
Basic Section 54010:Hematology and medical oncology-related
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Research Institution | Dokkyo Medical University |
Principal Investigator |
Mitani Kinuko 獨協医科大学, 医学部, 教授 (50251244)
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Co-Investigator(Kenkyū-buntansha) |
佐々木 光 獨協医科大学, 医学部, 准教授 (60282638)
市川 幹 獨協医科大学, 医学部, 准教授 (60463840)
中村 由香 獨協医科大学, 医学部, 講師 (80364595)
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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 |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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Keywords | RUNX1-EVI1 / t(3;21) / 急性巨核芽球性白血病 / SKP2 / ヒストン脱アセチル化酵素阻害剤 / 内科 / 癌 / 遺伝子 / 分子標的療法 |
Outline of Research at the Start |
急性骨髄性白血病の発症及び慢性骨髄性白血病や骨髄異形成症候群等の造血幹細胞腫瘍の白血病化には、転写因子遺伝子の機能異常が重要な役割を果たしている。本研究においては、これらの原因遺伝子RUNX1-EVI1の機能を、モデルマウスを使用して個体レベルで解析する。モデルマウスは移植実験によって得られたもので、急性巨核芽球性白血病を発症する。具体的には、RUNX1-EVI1の標的遺伝子の同定を行うとともに、白血病細胞の生存を支持している造血微小環境のニッチの機能を合わせて解析する。最終的には、これらの知見をもとにして、RUNX1-EVI1を標的とした分子治療の開発を目指す。
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Outline of Final Research Achievements |
RUNX1-EVI1 is a chimeric transcription factor generated by t(3;21) and causes the development of acute megakaryoblastic leukemia or transformation of chronic myelocytic leukemia and myelodysplastic syndrome. We created RUNX1-EVI1-type model mice by retroviral infection and transplantation experiments. By using primary leukemic cells derived from the mice, we investigated whether SKP2 is one of downstream targets for RUNX1-EVI1. Retroviral introduction of SKP2 inhibited their proliferation in cell culture, indicating that SKP2 could be a novel target of molecular therapy for RUNX1-EVI1-type leukemia.
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Academic Significance and Societal Importance of the Research Achievements |
RUNX1-EVI1型白血病は極めて予後が不良であり、化学療法のみでは治癒は困難である。今回作製されたモデルマウスを解析することにより、予後不良の白血病の発症機構が詳細に解明されることが期待される。また、これらの知見を基にして、今後新規の分子標的療法の開発が可能となる。RUNX1-EVI1はキメラ型転写因子でありヒストン脱アセチル化酵素阻害剤は有力な治療候補薬となるが、今後SKP2を標的とした分子標的療法が開発されることが期待される。
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Report
(4 results)
Research Products
(17 results)
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[Journal Article] Emergence of t(3;21)(q26.2;q22) during eltrombopag treatment in a patient with relapsed aplastic anemia who received chemotherapy for angioimmunoblastic T-cell lymphoma.2022
Author(s)
Nakamura F, Nakamura Y, Nannya Y, Arai H, Shimbo K, Nakamura Y, Seo S, Sasaki K, Ichikawa M, Ogawa S, Mitani.
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Journal Title
Leukemia Research Reports
Volume: 17
Pages: 100305-100305
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] PECAM is an effective and safe anthracycline-containing regimen for patients with relapsed or refractory non-Hodgkin lymphoma.2021
Author(s)
Nakamura F, Arai H, Tokita K, Furuichi S, Sugita-Nagasawa F, Takahashi W, Handa T, Iso H, Tadokoro J, Tsurumi S, Nakamura Y, Nakamura Y, Sasaki K, Seo S, Ichikawa M, Mitani K.
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Journal Title
Leukemia & Lympho
Volume: 62
Issue: 1
Pages: 239-242
DOI
Related Report
Peer Reviewed
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[Journal Article] Clonal hematopoiesis in adult pure red cell aplasia2021
Author(s)
Fujishima N、Kohmaru J、Koyota S、Kuba K、Saga T、Omokawa A、Moritoki Y、Ueki S、Ishida F、Nakao S、Matsuda A、Ohta A、Tohyama K、Yamasaki H、Usuki K、Nakashima Y、Sato S、Miyazaki Y、Nannya Y、Ogawa S、Sawada K、Mitani K、Hirokawa M
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Journal Title
Scientific Reports
Volume: 11
Issue: 1
Pages: 2253-2253
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Development of Philadelphia chromosome-negative acute myeloid leukemia with IDH2 and NPM1 mutations in a patient with chronic myeloid leukemia who showed a major molecular response to tyrosine kinase inhibitor therapy.2021
Author(s)
Nakamura F, Arai H, Nannya Y, Ichikawa M, Furuichi S, Nagasawa F, Takahashi W, Handa T, Nakamura Y, Tanaka H, Nakamura Y, Sasaki K, Miyano S, Ogawa S, Mitani K.
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Journal Title
Int J Hematol
Volume: 113
Issue: 6
Pages: 936-940
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] . Efficacy and safety of romiplostim in refractory aplastic anaemia: a Phase II/III, multicentre, open-label study.2020
Author(s)
Jang JH, Tomiyama Y, Miyazaki K, Nagafuji K, Usuki K, Uoshima N, Fujisaki T, Kosugi H, Matsumura I, Sasaki K, Kizaki M, Sawa M, Hidaka M, Kobayashi N, Ichikawa S, Yonemura Y, Enokitani K, Matsuda A, Ozawa K, Mitani K, Lee JW, Nakao S.
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Journal Title
Br J Haematol.
Volume: 192
Issue: 1
Pages: 190-199
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] The lysophospholipase D enzyme Gdpd3 is required to maintain chronic myelogenous leukaemia stem cells.2020
Author(s)
Naka K, Ochiai R, Matsubara E, Kondo C, Yang KM, Hoshii T, Araki M, Araki K, Sotomaru Y, Sasaki K, Mitani K, Kim D-W, Ooshima A, Kim SJ.
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Journal Title
Nature Comm
Volume: 11
Issue: 1
Pages: 4681-4681
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Continuous lenalidomide treatment after bortezomib-melphalan-prednisolone therapy for newly diagnosed multiple myeloma.2020
Author(s)
Ishida T, Hideo Kimura H, Ozaki S, Kubo K, Sunami K, Takezako N, Fujita H, Hayashi8 T, Toru Kiguchi T, Ohashi K, Yamamoto S, Takamatsu H, Kosugi H, Ohta K, Sakai R, Handa H, Kondo Seiji, Abe Y, Omoto E, Mitani K, Morita S, Murakami H, Shimizu K.
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Journal Title
Annals of Hematology
Volume: -
Issue: 5
Pages: 1063-1072
DOI
Related Report
Peer Reviewed
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[Presentation] ASXL1 mutations predict a poor response to darbepoetin alfa in anemic patients with low-risk MDS.2020
Author(s)
Hirohiko Shibayama, Yasuyoshi Morita, Motoshi Ichikawa, Yasuhito Nannya, Hitoshi Hanamoto, Yoshinobu Maeda, Tomoko Hata, Toshihiro Miyamoto, Hiroshi Kawabata, Kazuto Takeuchi, Hiroko Tanaka, Junji Kishimoto, Satoru Miyano, Itaru Matsumura, Seishi Ogawa, Koichi Akashi, Yuzuru Kanakura, Kinuko Mitani
Organizer
第82回日本血液学会学術集会総会
Related Report
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[Presentation] Prognostic Relevance of Genetic Abnormalities in Blastic Transformation of Chronic Myeloid Leukemia.2020
Author(s)
Yotaro Ochi, Kenichi Yoshida, Ko Sasaki, Yasuhito Nannya, Hideki Makishima, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Masashi Sanada, Satoru Miyano, Kinuko Mitani, Seishi Ogawa, et al.
Organizer
第62回米国血液学会
Related Report
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[Presentation] ASXL1 Mutations Predict a Poor Response to Darbepoetin Alfa in Anemic Patients with Low-risk MDS: A Multicenter, Phase II Study.2020
Author(s)
Hitoshi Hanamoto, Yasuyoshi Morita, Motoshi Ichikawa, Yasuhito Nannya, Hirohiko Shibayama, Yoshinobu Maeda, Tomoko Hata, Toshihiro Miyamoto, Hiroshi Kawabata, Kazuto Takeuchi, Hiroko Tanaka, Junji Kishimoto, Satoru Miyano, Itaru Matsumura, Seishi Ogawa, Koichi Akashi, Yuzuru Kanakura, Kinuko Mitani.
Organizer
第62回米国血液学会
Related Report
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