Identification of human acute leukemia specific metabolic pathways
| Project/Area Number |
19H03687
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | Kyushu University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
赤司 浩一 九州大学, 医学研究院, 教授 (80380385)
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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 |
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
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| Keywords | 白血病幹細胞 / がん代謝 / 代謝 / ミトコンドリア / アミノ酸代謝 |
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| Outline of Research at the Start |
ヒト急性骨髄性白血病(AML)および急性リンパ球性白血病（ALL)に共通する白血病幹細胞性維持機構として、腫瘍特異的代謝特性に着目して研究を行う。先行研究において、ヒト正常および悪性造血幹細胞のメタボロームデータベースの構築に取り組んでおり本研究においても、さらに症例数を増加させてデータベースの拡充を行う。さらにこれらのデータベースより、すでにAMLとALLに共通する代謝特性として、分岐鎖アミノ酸(BCAA)代謝経路の恒常的活性化を見出しており、本研究計画においてその幹細胞性維持制御機構について解析を行うことで、新規の白血病幹細胞特異的な代謝特性を標的とした新規治療法の確立を目指す。
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| Outline of Final Research Achievements |
In the current study, we explored the critical metabolic mechanisms underlying the maintenance of stem cell properties in human acute leukemia. Through the analysis of metabolome data sets we have established, we found that human CD34+ acute leukemia cells exhibited significantly higher cellular content of branched chain amino acids (BCAAs) as compared to normal CD34+ hematopoietic stem progenitor cells. Inhibition of BCAA metabolism strongly impaired the maintenance of leukemic stem cell properties of human acute leukemia in the xenograft models. Furthermore, we explored the molecular machineries how BCAA metabolism regulate the stemness of human acute leukemia and demonstrated that BCAA metabolism is specifically required to maintain PRC2 components including EZH2 and EED. Thus, BCAA metabolism represents a specific regulator of stem cell properties via maintaining PRC2 function in human acute leukemia.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究の遂行により、ヒト急性白血病における幹細胞性維持にとって重要な代謝特性としてBCAA代謝経路を同定することができた。また、BCAA代謝が利用する幹細胞性維持機構として、下流のPRC2機能制御を同定することができた。これらの結果から、BCAA代謝経路を標的としたヒト急性白血病における治療戦略を構築する上で、基盤的な特性を明らかにすることができた。したがって本研究の果たした意義は基礎的研究分野のみならず、今後の応用も含めた発展性のある内容であり、社会的意義も高いものであると考える。
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Report
(4 results)
Research Products
(21 results)
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[Journal Article] A Germinal Center-Associated Microenvironmental Signature Reflects Malignant Phenotype and Outcome of DLBCL.2022
Author(s)
Miyawaki K, Kato K, Sugio T, Sasaki K, Miyoshi H, Semba Y, Kikushige Y, Mori Y, Kunisaki Y, Iwasaki H, Miyamoto T, Kuo FC, Aster JC, Ohshima K, Maeda T, Akashi K.
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Journal Title
Blood Adv.
Volume: 6
Issue: 7
Pages: 2388-2402
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Aromatase is a novel neo-substrate of cereblon responsible for immunomodulatory drugs-induced thrombocytopenia. Tochigi T, Miyamoto T, Hatakeyama K, Sakoda T, Ishihara D, Irifune H, Shima T, Kato K, Maeda T, Ito T, Handa H, Akashi K, Kikushige Y.2020
Author(s)
Tochigi T, Miyamoto T, Hatakeyama K, Sakoda T, Ishihara D, Irifune H, Shima T, Kato K, Maeda T, Ito T, Handa H, Akashi K, Kikushige Y.
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Journal Title
Blood.
Volume: -
Issue: 24
Pages: 2146-2158
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Generation of a novel CD30 + B cell subset producing GM-CSF and its possible link to the pathogenesis of systemic sclerosis2020
Author(s)
Higashioka K, Kikushige Y, Ayano M, Kimoto Y, Mitoma H, Kikukawa M, Akahoshi M, Arinobu Y, Horiuchi T, Akashi K, Niiro H.
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Journal Title
Clin Exp Immunol.
Volume: 201
Issue: 3
Pages: 233-243
DOI
Related Report
Peer Reviewed
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[Journal Article] TKIs induce alternative spliced BCR-ABLIns35bp variant via inhibition of RNA polymerase Ⅱ on genomic BCR-ABL.2020
Author(s)
Yuda J, Odawara J, Minami M, Muta T, Kohno K, Tanimoto K, Eto T, Shima T, Kikushige Y, Kato K, Takenaka K, Iwasaki H, Minami Y, Ohkawa Y, Akashi K, Miyamoto T.
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Journal Title
Cancer Sci
Volume: 111
Issue: 7
Pages: 2361-2373
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Anti-GPRC5D/CD3 Bispecific T-Cell-Redirecting Antibody for the Treatment of Multiple Myeloma.2019
Author(s)
Kodama T, Kochi Y, Nakai W, Mizuno H, Baba T, Habu K, Sawada N, Tsunoda H, Shima T, Miyawaki K, Kikushige Y, Mori Y, Miyamoto T, Maeda T, Akashi K.
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Journal Title
Molecular Cancer Therapeutics
Volume: 18
Issue: 9
Pages: 1555-1564
DOI
Related Report
Peer Reviewed
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