Molecular mechanisms of lower-risk MDS
Project/Area Number |
19K08824
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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 | Tokyo University of Pharmacy and Life Science |
Principal Investigator |
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Co-Investigator(Kenkyū-buntansha) |
原田 結花 東京都立駒込病院(臨床研究室), 臨床試験科, 部長 (50379848)
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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 | 骨髄異形成症候群 / 骨髄不全症 / RUNX1 / ミトコンドリア動態異常 / BMTモデル / モデルマウス / ミトコンドリア機能動態 / RUNX1変異 |
Outline of Research at the Start |
骨髄異形成症候群(MDS)は造血幹細胞の異常に起因する難治性血液がんである。病態の本質は異常クローンの腫瘍性増殖とアポトーシス亢進、正常クローン抑制による骨髄不全症はであるが、詳細な発症機序は不明である。我々は新規に骨髄不全MDSマウスモデルを作製し、造血細胞でのミトコンドリア関連遺伝子群の有意な発現亢進を見出した。この遺伝子発現変化が骨髄不全MDS患者群に特徴的であることを遺伝子発現データベース解析により確認した。本研究では、新規モデルマウスを用いたin vivo解析や患者検体を用いた検証を通じて、MDS腫瘍クローンのミトコンドリア機能動態変化による骨髄不全症発症機序を解明する。
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Outline of Final Research Achievements |
Myelodysplastic syndromes (MDS) are defined as stem cell disorders caused by various gene abnormalities. Recent analysis has provided advances in identifying relationships between mutations and clinical phenotypes. However, the mechanism of ineffective hematopoiesis, which is a fundamental process leading to the clinical feature, remain unclear. Therefore, we investigated the molecular mechanism using CBLΔE8/9/RUNX1S291fs mice. RNA-Seq revealed that a distinct gene expression profile of MDS patients is induced in this model. We identified the DRP1-dependent mitochondrial fragmentation as a trigger of MDS pathogenesis. Notably, the fragmentation is observed in HSCs from patients regardless of mutational profile. Pharmacological inhibition of DRP1 activity attenuated dysplasia and ineffective hematopoiesis, and prolonged survival of mice. Our results provide new insights into ineffective hematopoiesis and indicate that dysregulated mitochondrial dynamics could be a druggable target.
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Academic Significance and Societal Importance of the Research Achievements |
MDSに関わる多数の遺伝子変異が同定されたが、発症や進展の分子病態は不明である。前白血病といわれているMDSは白血病と同様、遺伝子変異が造血幹細胞に生じているが、徐々に進行する汎血球減少と白血病へ移行する特有な病態は明らかになっていない。臨床的には、貧血などの血球減少への対応が中心となる低リスクMDSと白血病移行の抑制が治療の主体となる高リスクMDSに分類される。MDS治療薬であるアザシチジンは高リスクが対象であり、MDSの主病態である汎血球減少症に対する治療薬はない。本研究成果は、MDSの多様な遺伝子変異に共通する分子病態を明らかにしたことにより、新たなMDSの創薬開発に繋がったといえる。
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Report
(4 results)
Research Products
(65 results)
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[Journal Article] Inhibition of BCL2A1 by STAT5 inactivation overcomes resistance to targeted therapies of FLT3-ITD/D835 mutant AML2022
Author(s)
Yamatani K, Ai T, Saito K, Suzuki K, Hori A, Kinjo S, Ikeo K, Ruvolo V, Zhang W, Mak PY, Kaczkowski B, Harada H, Katayama K, Sugimoto Y, Myslinski J, Hato T, Miida T, Konopleva M, Hayashizaki Y, Carter BZ, Tabe Y, Andreeff M
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Journal Title
Translational Oncology
Volume: 18
Pages: 101354-101354
DOI
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Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Genetic basis for iMCD-TAFRO2020
Author(s)
Yoshimi Akihide、Trippett Tanya M.、Zhang Nan、Chen Xueyan、Penson Alexander V.、Arcila Maria E.、Pichardo Janine、Baik Jeeyeon、Sigler Allison、Harada Hironori、Fajgenbaum David C.、Dogan Ahmet、Abdel-Wahab Omar、Xiao Wenbin
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Journal Title
Oncogene
Volume: -
Issue: 15
Pages: 3218-3225
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Late appearance of eosinophilia in myeloid blast phase of myeloid neoplasm with rearrangement of PDGFRβ2020
Author(s)
Nagata A, Doki N, Harada H, Takezaki T, Konishi T, Yamada Y, Kaito S, Kurosawa S, Yoshifuji K, Harada K, Sakaguchi M, Yasuda S, Yoshioka K, Watakabe-Inamoto K, Toya T, Igarashi A, Najima Y, Muto H, Kobayashi T, Kakihana K, Harada Y, Sakamaki H, Ohashi K
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Journal Title
Leukemia & Lymphoma
Volume: -
Issue: 7
Pages: 1-4
DOI
Related Report
Peer Reviewed
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[Presentation] Mutation Analysis of Very Late Relapse of Myeloid Malignancies after Stem Cell Transplantation2021
Author(s)
Takashi Toya, Daichi Sadato, Yasuhiro Kanbara, Chizuko Hirama, Kyoko Haraguchi, Hiroaki Shimizu, Yuho Najima, Takeshi Kobayashi, Yoshiki Okuyama, Keisuke Oboki, Hironori Harada, Kazuteru Ohashi, Yuka Harada, Noriko Doki
Organizer
The 12th JSH International Symposium 2021
Related Report
Int'l Joint Research
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[Presentation] 同種造血幹細胞移植後晩期発症 EBV 関連リンパ増殖性疾患としての Burkitt リンパ腫の一例2021
Author(s)
内堀雄介, 遠矢嵩, 貞任大地, 平間千津子, 神原康弘, 熱田雄也, 須崎賢, 安達弘人, 小沼亮介, 和田敦司, 岸田侑也, 野口侑真, 丸毛淳史, 迎純一, 新谷直樹, 五十嵐愛子, 清水啓明, 名島悠峰, 小林武, 坂巻 壽, 大保木啓介, 原田浩徳, 大橋一輝, 原田結花, 土岐 典子
Organizer
第43回日本造血細胞移植学会総会
Related Report
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[Presentation] 同種移植後長期生存者のクローン造血2021
Author(s)
内堀雄介, 遠矢嵩, 貞任大地, 平間千津子, 神原康弘, 熱田雄也, 須崎賢, 安達弘人, 小沼亮介, 和田敦司, 岸田侑也, 野口侑真, 丸毛淳史, 迎純一, 新谷直樹, 五十嵐愛子, 清水啓明, 名島悠峰, 小林武, 坂巻 壽, 大保木啓介, 原田浩徳, 大橋一輝, 原田結花, 土岐 典子
Organizer
第43回日本造血細胞移植学会総会
Related Report
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[Presentation] Clinical and Genetic Characteristics of Adolescent and Young Adult Patients with Myelodysplastic Syndromes2019
Author(s)
Konishi T, Harada Y, Sadato D, Otsuka Y, Konuma R, Adachi H, Wada A, Kishida Y, Nagata A, Yamada Y, Marumo A, Noguchi Y, Mukae J, Inamoto K, Toya T, Igarashi A, Najima Y, Kobayashi T, Kakihana K, Haraguchi K, Okuyama Y, Harada H, Ohashi K, Doki N
Organizer
The 61th ASH Annual Meeting and Exposition
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[Presentation] Cage Transcriptome Analysis Reveals BCL2A1 Upregulation in FLT3-ITD/D835 Dual Mutated AML Cells Harboring Complex Co-Mutations2019
Author(s)
Yamatani K, Ai T, Saito K, Yang H, Suzuki K, Hori A, Murakami-Tonami Y, Zhang W, Carter BZ, Kinjo S, Ikeo K, Katayama K, Harada H, Miida T, Shah NP, Konopleva MY, Hayashizaki Y, Andreeff M, Tabe Y
Organizer
The 61th ASH Annual Meeting and Exposition
Related Report
Int'l Joint Research
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[Presentation] rospective Comparison of Azacitidine Treatment between 7-Days and 5-Days Schedules for Patients with Higher-Risk Myelodysplastic Syndromes; Results of Japan Adult Leukemia Study Group MDS212 Trial2019
Author(s)
Kiguchi T, Sato S, Usuki K, Ishiyama K, Ito Y, Suzuki T, Taguchi J, Chiba S, Dobashi N, Tomita A, Harada H, Handa H, Horiike S, Maeda T, Matsuda M, Ichikawa M, Hata T, Honda S, Iyama S, Suzushima S, Moriuchi Y, Kurokawa T, Yamauchi T, Kiyoi H, Naoe T, Miyazaki Y
Organizer
The 61th ASH Annual Meeting and Exposition
Related Report
Int'l Joint Research
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