Molecular pathogenesis of familial myelodysplastic syndromes
Project/Area Number |
16K09831
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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 |
Research Field |
Hematology
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Research Institution | Tokyo Metropolitan Komagome Hospital (Clinical research laboratory) (2018) Bunkyo Gakuin University (2016-2017) |
Principal Investigator |
HARADA Yuka 東京都立駒込病院(臨床研究室), 臨床試験科, 医長 (50379848)
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Co-Investigator(Kenkyū-buntansha) |
原田 浩徳 東京薬科大学, 生命科学部, 教授 (10314775)
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Project Period (FY) |
2016-04-01 – 2019-03-31
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Project Status |
Completed (Fiscal Year 2018)
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Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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Keywords | 家族性造血器腫瘍 / 骨髄異形成症候群(MDS) / ターゲットシークエンス / RUNX1変異 / TP53変異 / マウス骨髄移植モデル / マウスBMTモデル / 癌 |
Outline of Final Research Achievements |
Germline predisposition is increasingly recognized in myelodysplastic syndromes (MDS). We found 20 pedigrees of myeloid neoplasms and analyzed the mutations of RUNX1, CEBPA, GATA2 and DDX41 genes. Using Sanger sequencing and target sequencing by next generation sequencing, only 6 pedigrees were identified their responsible gene mutations. The responsible gene mutations could not be identified in other 14 pedigrees, suggesting that there still may exist many potential pedigrees of familial myeloid neoplasms caused by unknown gene mutations. We identified a collaboration partner gene, Gene Y, which was detected in iPS cells from RUNX1-mutated pedigree. Co-transduction of a RUNX1-mutant and Gene Y in mouse bone marrow transplantation model developed MDS with severe anemia in a few months. Therefore, we suspected that a RUNX1 mutation is one of the stem cell aging factors.
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Academic Significance and Societal Importance of the Research Achievements |
家族性造血器腫瘍20家系のうち、既知の原因遺伝子のうちいずれかの変異を認めた家系は少数にとどまり、大半の症例で原因遺伝子変異が同定されなかったことから、germline変異の原因遺伝子変異として知られているものは一部に過ぎず、潜在的に多くの家系が未知の遺伝子異常により家族性造血器腫瘍を発症していることが示唆された。また、RUNX1変異自体が分化障害を有し、Gene Yと協調して非常に短期間でMDSを発症することから、RUNX1変異自体がエイジング因子であると考えられた。
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Report
(4 results)
Research Products
(65 results)
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[Journal Article] Spectrum of clinical and genetic features of patients with inherited platelet disorder with suspected predisposition to hematological malignancies: a nationwide survey in Japan.2016
Author(s)
Yoshimi A, Toya T, Nannya Y, Takaoka K, Kirito K, Ito E, Nakajima H, Hayashi Y, Takahashi T, moriya-Saito A, Suzuki K, Harada H, Komatsu N, Usuki K, Ixhikawa M, Kurokawa M.
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Journal Title
Annals of Oncology
Volume: 27
Issue: 5
Pages: 887-895
DOI
Related Report
Peer Reviewed / Open Access
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[Presentation] Prognostic value of TP53 mutation and monosomal karyotype for AML in non-remission at allo-HCT2019
Author(s)
14.Najima Y, Sadato D, Hirama C, Harada Y, Oboki K, Toya T, Doki N, Haraguchi K, Adachi H, Konuma R, Fujita M, Wada A, Kishida Y, Konishi T, Nagata A, Yamada Y, Kaito S, Yoshifuji K, Akiyama M, Inamoto K, Igarashi A, Kobayashi T, Kakihana K, Okuyama Y, Sakamaki H, Harada H, Ohashi K
Organizer
第41回日本造血細胞移植学会総会
Related Report
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[Presentation] NUP98-HBO1 Induces Clinically Relevant CMML Pathogenesis through Aberrant Histone Acetylation2018
Author(s)
Hayashi Y, Harada Y, Kagiyama Y, Matsui H, Kato N, Ding Y, Imagawa J, Kitaura J, Kitabayashi I, Iwama A, Kitamura T, Harada H
Organizer
第80回日本血液学会学術集会
Related Report
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[Presentation] Presence of TP53 mutation and monosomal karyotype predict the outcome of patients with acute myeloid leukemia in non-remission at allogeneic stem cell transplantation2018
Author(s)
9.Najima Y, Oboki K, Harada Y, Sadato D, Hirama C, Toya T, Doki N, Haraguchi K, Kobayashi T, Kakihana K, Inamoto K, Okuyama Y, Sakamaki H, Harada H, Ohashi K
Organizer
60th ASH Annual Meeting and Exposition
Related Report
Int'l Joint Research
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[Presentation] HIF1Aシグナルの亢進は骨髄異形成症候群の病態形成において中心的な役割を果たす2017
Author(s)
林嘉宏, Zhang Y, Yan Z, 指田吾郎, Chetai K, Olsson A, 原田浩徳, Shih L-Y, Tse W, Bridges J, Zheng Y, Witte D, Caligiuri M, Qu C-K, Whang Q-F, Salomonis N, Grimes HL, Nimer S, Xiao Z, Huang G
Organizer
第79回日本血液学会学術集会
Related Report
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[Presentation] XPO1 inhibition targets transcriptional vulnerability of FLT3-ITD+D835 double mutant AML through p53 accumulation and inhibition of oncogenic transcription factors: Lesson learned from CAGE sequencing of primary AML cells2017
Author(s)
Yamatani K, Tabe Y, Sekihara K, Yang H, Saitoh K, Zhang W, Ikeo K, Kinjo S, Mogushi K, Hosoya M, Hayashizaki Y, Yamanaka Y, Harada H, Miida T, Konopleva M, Andreeff M
Organizer
59th ASH Annual Meeting and Exposition
Related Report
Int'l Joint Research
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[Presentation] Human Germline HLTF E259K Mutation Identified in Familial MDS Patients Accumulates DNA Damage through Impaired PCNA Polyubiquitination2017
Author(s)
Takaoka K, Kawazu M, Koya J, Yoshimi A, Masamoto Y, Maki H, Toya T, Kobayashi T, Nannya Y, Arai S, Ueno H, Suzuki K, Harada H, Manabe A, Hayashi Y, Mano H, Kurokawa M
Organizer
59th ASH Annual Meeting and Exposition
Related Report
Int'l Joint Research
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[Presentation] Disordered Gene Expression in Hematologic Malignancy,including Disordered Epigenetic Regulation2016
Author(s)
Tabe Y, Sekihara K, Saitoh K, Monma N, Ikeo K, Kaczkowski B, Zhang W, Yamanaka Y, Miida T, Shah N, Harada H, Hayashizaki Y, Konopleva M, Andreeff M
Organizer
58th ASH Annual Meeting and Exposition
Place of Presentation
SanDiego, CA (USA)
Year and Date
2016-12-03
Related Report
Int'l Joint Research
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[Presentation] Nationwide epidemiological surver of familial myelodysplastic syndromes/acute myeloid leukemia in Japan2016
Author(s)
Takaoka K, Yoshimi A, Koya J, Toya T, Kobayashi T, Nannya Y, Ueno H, Suzuki K, Harada H, Manabe A, Hayashi Y, Kurokawa M
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)
Year and Date
2016-10-13
Related Report
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[Presentation] Analysis of Asxl1-MT conditional knock-in mice2016
Author(s)
Nagase R, Inoue D, Kanai A, Saika M, Fujino T, Kawabata K, Tanaka Y, Fukuyama T, Harada H, Goyama S, Honda H, Kitamura T
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)
Year and Date
2016-10-13
Related Report
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[Presentation] Expansion of ABCG2 is regulated in EZH2-related MDS and associated with its pathogenesis2016
Author(s)
Kawabata K, Hayashi Y, Inoue D, Sakurai H, Mizuno H, Kitaura J, Harada Y, Harada H, Goyama S, Aburatani H, Ishii M, Kitamura T
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)
Year and Date
2016-10-13
Related Report
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[Presentation] 家族性骨髄異形成症候群/急性骨髄性白血病の本邦における疫学2016
Author(s)
Takaoka K, Yoshimi A, Koya J, Kobayashi T, Ueno H, Suzuki K, Harada H, Manabe A, Hayashi Y, Kurokawa M
Organizer
第14回日本臨床腫瘍学会学術集会
Place of Presentation
神戸国際会議場(兵庫県神戸市)
Year and Date
2016-07-28
Related Report
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