2016 Fiscal Year Research-status Report
骨髄間葉系間質細胞を標的とした前駆B細胞性急性白血病治療に関する検討
| Project/Area Number |
15K09453
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| Research Institution | Kyoto University |
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Principal Investigator |
三浦 康生 京都大学, 医学研究科, 助教 (70605146)
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| Project Period (FY) |
2015-04-01 – 2018-03-31
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| Keywords | 急性リンパ性白血病 / 間葉系間質細胞 / 間葉系幹細胞 / 抗がん剤抵抗性 / 細胞接着 |
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| Outline of Annual Research Achievements |
前年度の研究で，ヒト前駆B細胞性急性リンパ性白血病細胞（B cell precursor acute lymphoblastic leukemia: BCP-ALL）はヒト骨髄間葉系間質細胞（Bone marrow mesenchymal stromal/stem cell: BM-MSC）と接着することで，抗がん剤抵抗性が増強することを明らかにし，BCP-ALL患者の治療においては，白血病細胞のみではなく，白血病細胞の周辺環境を構成するBM-MSCが治療標的となり得ることを示した．
本年度の研究では，BM-MSCに作用し，BCP-ALL細胞との接着性を減弱する薬剤の検討を行った．その結果，ボルテゾミブおよび他の2つのプロテアソーム阻害剤が有望であることを確認した．BM-MSCをこれらの薬物で刺激し，BCP-ALL細胞と共培養すると，BCP-ALL細胞との接着性が減弱した．そして，BCP-ALL細胞は，細胞周期に変化が見られ，細胞生存シグナル分子Aktのリン酸化や抗アポトーシス分子Bcl-2の発現が低下していた．従って，ボルテゾミブなどのプロテアソーム阻害剤はBM-MSCに作用することでBCP-ALL細胞との接着性を減弱させ，その結果BCP-ALL細胞の抗がん剤感受性を回復させることが明らかとなった．
以上より，BCP-ALL患者の治療においては，プロテアソーム阻害剤を用いたBM-MSCを標的とする治療戦略が有効である可能性をin vitroの検証で示した．
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| Current Status of Research Progress |
Current Status of Research Progress
1: Research has progressed more than it was originally planned.
Reason
既に次年度に予定していた研究計画の一部に取り組んでいる．
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| Strategy for Future Research Activity |
今年度に得られたデータをもとに，プロテアソーム阻害剤がBCP-ALLの治療に有効であることを，BCP-ALLモデルマウスを作成し応用することで検討する．
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| Causes of Carryover |
研究が順調に進捗し，物品費が当初見込みより節減できたため
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| Expenditure Plan for Carryover Budget |
次年度に計画されているコストのかかるマウスモデルを用いた研究に充当することで研究遂行を加速させる．
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[Journal Article] Genotyping of relapsing polychondritis identified novel susceptibility HLA alleles and distinct genetic characteristics from other rheumatic diseases.2016
Author(s)
Terao C, Yoshifuji H, Yamano Y, Kojima H, Yurugi K, Miura Y, Maekawa T, Handa H, Ohmura K, Saji H, Mimori T, Matsuda F.
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Journal Title
Rheumatology
Volume: 55
Pages: 1686-1692
DOI
Peer Reviewed
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[Presentation] Late Adherent Subpopulation in Umbilical Cord Blood Has the Same Characteristics and Hematopoiesis-Supporting Capacity As Mesenchymal Stromal/Stem Cells.2016
Author(s)
Yoshioka S, Miura Y, Iwasa M, Fujishiro A, Sugino N, Fujii S, Nakagawa Y, Sato A, Yokota A, Hirai H, Ichinohe T, Takaori-Kondo A, Maekawa T.
Organizer
American Society of Hematology, 58th Annual Meeting
Place of Presentation
San Diego, CA, USA
Year and Date
2016-12-02 – 2016-12-05
Int'l Joint Research
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[Presentation] C/EBPβ Is a Critical Regulator of CML Stem Cell Differentiation and Exhaustion Induced By Interferon-α.2016
Author(s)
Yokota A, Hirai H, Hayashi Y, Sato R, Adachi H, Sato F, Sato A, Tamura A, Iwasa M, Fujishiro A, Shoji T, Kashiwagi T, Kamio N, Torikoshi Y, Miura Y, Nakano M, Tashiro K, Maekawa T.
Organizer
American Society of Hematology, 58th Annual Meeting
Place of Presentation
San Diego, CA, USA
Year and Date
2016-12-02 – 2016-12-05
Int'l Joint Research
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[Presentation] C/EBPβ Is Required for Survival of Ly6C- Monocytes after Committment to Monocyte Lineage through Upregulation of Csf1r.2016
Author(s)
Tamura A, Hirai H, Yokota A, Kamio N, Sato A, Shoji T, Kashiwagi T, Iwasa M, Fujishiro A, Miura Y, Maekawa T.
Organizer
American Society of Hematology, 58th Annual Meeting
Place of Presentation
San Diego, CA, USA
Year and Date
2016-12-02 – 2016-12-05
Int'l Joint Research
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[Presentation] Vitamin K2 supports hematopoiesis through acting on human bone marrow mesenchymal stromal/stem cells.2016
Author(s)
Fujishiro A, Miura Y, Iwasa M, Fujii S, Sugino N, Sato A, Yokota A, Hirai H, Andoh A, Tohyama K, Ichinohe T, Maekawa T.
Organizer
The 78th Annual Meeting of the Japanese Society of Hematology
Place of Presentation
横浜
Year and Date
2016-10-14 – 2016-10-14
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[Presentation] The C/EBPβ transcription factor mediates exhaustion of CML stem cells induced by IFNα.2016
Author(s)
Yokota A, Hirai H, Sato A, Tamura A, Shoji T, Kashiwagi T, Fujishiro A, Iwasa M, Miura Y, Hayashi Y, Maekawa T.
Organizer
The 78th Annual Meeting of the Japanese Society of Hematology
Place of Presentation
横浜
Year and Date
2016-10-14 – 2016-10-14
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[Presentation] Human bone marrow mesenchymal stromal/sem cells modulate IMiDs-induced differentiation of HSPCs.2016
Author(s)
Fujii S, Miura Y, Iwasa M, Fujishiro A, Sugino N, Sato A, Yokota A, Hirai H, Takaori-Kondo A, Ichinohe T, Maekawa T.
Organizer
The 78th Annual Meeting of the Japanese Society of Hematology
Place of Presentation
横浜
Year and Date
2016-10-13 – 2016-10-13
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[Presentation] The C/EBPβ transcription factor promotes exhaustion of CML stem cells in response to interferon-α.2016
Author(s)
Yokota A, Hirai H, Hayashi Y, Sato R, Adachi H, Sato F, Sato A, Tamura A, Miura Y, Nakano M, Tashiro K, Maekawa T.
Organizer
第75回日本癌学会学術総会
Place of Presentation
横浜
Year and Date
2016-10-06 – 2016-10-08
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[Presentation] The C/EBPβ Transcription Factor Mediates the Effect of IFNα on CML Stem Cells Through Promoting Their Differentiation and Exhaustion.2016
Author(s)
Yokota A, Hirai H, Hayashi Y, Sato R, Adachi H, Sato F, Sato A, Tamura A, Iwasa M, Fujishiro A, Shoji T, Kashiwagi T, Miura Y, Nakano M, Tashiro K, Maekawa T.
Organizer
The 5th JCA-AACR Special Joint Conference
Place of Presentation
Urayasu, Chiba, Japan
Year and Date
2016-07-14
Int'l Joint Research
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