Elucidate the mechanism underlying the pediatric leukemogenesis associated with epigenetic alterations
Project/Area Number |
18K15687
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 52050:Embryonic medicine and pediatrics-related
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Research Institution | Tokai University (2020-2022) Showa University (2018-2019) |
Principal Investigator |
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Project Period (FY) |
2018-04-01 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
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Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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Keywords | 骨髄増殖性疾患 / 骨髄線維症 / 急性骨髄性白血病 / エピジェネティック制御関連遺伝子 / ASXL1遺伝子 / JAK2V617F / leukemogenesis / 骨髄異形成症候群 / ASXL1 / エピジェネティクス制御機構の破綻 / 骨髄繊維症 / エピジェネティック変異 / ASXL1遺伝子変異 / 本態性血小板血症 / ASXL1変異 / H3K27me3発現低下 / 小児AML / エピジェネティック制御機構 / 新規治療法開発 |
Outline of Final Research Achievements |
The somatic mutation of JAK2V617F is present in >95% of polycythemia vera (PV) patients. PV patients with co-mutations of epigenetic regulators such as ASXL1 and JAK2V617F occurred myelofibrosis (MF) with poor prognosis. Asxl1 loss accelerates MF in JAK2V617F-driven myeloproliferative neoplasm (MPN) in mice. JAK2V617F;Asxl1+/- mice induces megakaryocytic hyperplasia and can transform to myeloid leukemia. Haploinsufficiency of Asxl1 and JAK2V617F trigger myeloid leukemia transformation through an additive effect to enhance H3K4me3 levels in the promoter region with oncogene.
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Academic Significance and Societal Importance of the Research Achievements |
骨髄増殖性疾患はJAK2V617F変異を高頻度に認める疾患であるが、近年、ASXL1などのエピジェネティック制御に関わる遺伝子変異が協調することで予後不良な骨髄線維症や骨髄性白血病を発症すると考えられている。本研究では、ヒトにおける疾患の特徴を明らかにすると同時に、モデルマウスにおいても同様の事象を確認しえた。また、疾患発症のメカニズムを解明し、至適薬剤を検討することで新規治療法開発につなげることが可能となり社会的意義を有する研究である。
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Report
(6 results)
Research Products
(60 results)
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Mitsuteru Hiwatari1, 2, 3, Masafumi Seki1, Ryosuke Matsuno4, Kenichi Yoshida5, Takeshi Nagasawa1, Aiko Sato-Otsubo1, Shohei Yamamoto6, Motohiro Kato1, Kentaro Watanabe1, Masahiro Sekiguchi1, Satoru Miyano7, Seishi Ogawa5, 8, 9, and Junko Takita10
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Arakawa Y, Hasegawa D, Miyamura T, Oshima J, Kimura S, Imamura T, Koga Y, Yamamoto S, Ogawa A, Shinoda K, Nagai K, Hosoi H, Imai K, Koh K, Tomizawa D
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Pediatr Blood Cancer
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Author(s)
Yamamoto S, Kato M, Watanabe K, Ishimaru S, Hasegawa D, Noguchi M, Hama A, Sato M, Koike T, Iwasaki F, Yagasaki H, Takahashi Y, Kosawa Y, Hashii Y, Morimoto A, Atsuta Y, Hasegawa D, Yoshida N
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Bone Marrow Transplant
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[Journal Article] Hematopoietic stem cell transplantation for pediatric acute promyelocytic leukemia in Japan2020
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Author(s)
Akiyama K, Ikezawa S, Hasegawa Y, Sugisita Y, Kaneko R, Okamoto N, Koganesawa M, Fujita S, Matsuno R, Toyama D, Ikeda H, Yamamoto S
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Journal Title
Showa Univ J Med Sci
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[Journal Article] ASXL1 alteration cooperates with JAK2V617F to accelerate myelofibrosis2019
Author(s)
Guy Y, Zhou Y, Yamamoto S, Yang H, Zhang P, Chen S, Nimer SD, Zhao Z, Xu M, Bai J, Yang FC.
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Journal Title
Leukemia
Volume: 33
Issue: 5
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[Journal Article] Chemotherapy ineffective for sacral stage 3 neuroblastoma: treatment strategy for tumors of favorable histology type2019
Author(s)
松野良介, 大貫裕太, 杉下友美子, 金子綾太, 小金澤征也, 藤田祥央, 岡本奈央子, 秋山康介, 外山大輔, 池田裕一, 土岐 彰, 山本将平
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Journal Title
The Japanese Journal of Pediatric Hematology / Oncology
Volume: 56
Issue: 5
Pages: 459-463
DOI
NAID
ISSN
2187-011X, 2189-5384
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[Journal Article] Gain-of-function of ASXL1 truncating protein in the pathogenesis of myeloid malignancies2018
Author(s)
Yang H, Kurtenbach S, Guo Y, Lohse I, Durante MA, Li J, Li Z, Al-Ali H, Li L, Chen Z, Field MG, Zhang P, Chen S, Yamamoto S, Li Z, Zhou Y, Nimer SD, Harbour JW, Wahlestedt C, Xu M, Yang FC
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Journal Title
Blood
Volume: 131
Issue: 3
Pages: 328-341
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[Journal Article] Launch of “sweet home”, a group for parents of pediatric cancer patients2018
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Journal Title
The Japanese Journal of Pediatric Hematology / Oncology
Volume: 55
Issue: 2
Pages: 182-186
DOI
NAID
ISSN
2187-011X, 2189-5384
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[Journal Article] Initial presentation of lymphoblastic crisis in a pediatric chronic myelogenous leukemia patient2018
Author(s)
秋山康介, 山本将平, 杉下友美子, 金子綾太, 岡本奈央子, 小金澤征也, 藤田祥央, 松野良介, 外山大輔, 磯山恵一
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Journal Title
Rinsho Ketsueki
Volume: 59
Issue: 1
Pages: 75-79
DOI
NAID
ISSN
0485-1439, 1882-0824
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[Journal Article] Increased expression of interleukin-17 is associated with macrophages in chronic immune thrombocytopenia2018
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Okamoto N, Homma M, Kawaguchi Y, Kabasawa N, Uto Y, Hattori N, Yamamoto S, Shiozawa E, Yamochi T, Tate G, Isoyama K, Nakamaki T, Takimoto M
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Journal Title
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Volume: 11
Pages: 2419-2429
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[Journal Article] EVALUATION OF IL-17 EXPRESSION IN CHRONIC ITP USING IMMUNOHISTOCHEMICAL ANALYSIS2018
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Journal Title
Journal of The Showa University Society
Volume: 78
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2187-719X, 2188-529X
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