| Project/Area Number |
18K08367
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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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 | Kyoto Prefectural University of Medicine |
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Principal Investigator |
Kobayashi Tsutomu 京都府立医科大学, 医学(系)研究科(研究院), 講師 (00624793)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 多発性骨髄腫 / クローン進展 / BUB1 / SGO1 / 染色体分配異常 / B細胞性リンパ腫 / クローン性進展 / Shugoshin / 造血器腫瘍 |
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| Outline of Final Research Achievements |
This study revealed that mitotic checkpoint-associated molecules, BUB1 and SGO1, were overexpressed in patient-derived multiple myeloma (MM) cells and B-cell lymphoma cells (BCLs), especially in patients in an advanced stage. In myeloma cells and BCL cells, BUB1 knockdown reduced the frequency of chromosome segregation errors in mitotic cells and reduced resultant variations in chromosome number compared to parent cells. BUB1 knockdown also led myeloma cells and BCL cells to be more sensitive to microtubule inhibitors. Finally, BUB1 overexpression was found to promote the clonogenic potency. In contrast, the functional roles of SGO1 knockdown varied among cells, and were not prominent compared with those induced by BUB1 knockdown. Collectively, enhanced BUB1 expression caused an increase in mitotic segregation errors and the resultant emergence of subclones with altered chromosome numbers and, thus, was involved in chromosome instability in MM and BCLs.
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| Academic Significance and Societal Importance of the Research Achievements |
染色体不安定性に伴う染色体異常進展は、がんの病態悪化と治療抵抗性獲得を促進するダイナミックなメカニズムであるが、その制御戦略は未開発である。本研究では細胞分裂チェックポイント分子であり、本来、染色体分配異常を監視し、細胞分裂異常による染色体異常の獲得を抑止すべきBUB1やSGO1が骨髄腫細胞やB細胞性リンパ腫細胞で過剰発現しており、その発現レベルは病態悪化を示唆するバイオマーカーとして活用可能であることを見出した。さらに機能的解析によって、BUB1が多段階発がん過程の抑止を目指すうえでの創薬ターゲットとしての妥当性が示された点で、今後の応用が期待される研究成果と考える。
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