| Project/Area Number |
19K21281
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| Project/Area Number (Other) |
18H06173 (2018)
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Multi-year Fund (2019)
Single-year Grants (2018) |
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| Review Section |
0901:Oncology and related fields
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| Research Institution | Chiba University |
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Principal Investigator |
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| Project Period (FY) |
2018-08-24 – 2020-03-31
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| Project Status |
Declined (Fiscal Year 2019)
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| Budget Amount *help |
¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | multiple myeloma / EZH2 / UTX / UNC1999 / GSK126 / Multiple myeloma / Epigenetics |
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| Outline of Annual Research Achievements |
In this study, I investigated the biological role of UTX in multiple myeloma.
Using a murine cell line that we had developed from plasmacytic ascites derived from a moribund Utx -/- Braf V600E mouse, we successfully performed serial transplantation into NOG recipient mice.
Next, we investigated the susceptibility of our murine cell line to novel and conventional anti-myeloma agents. We found that dual inhibition of EZH2 and its homolog EZH1 using UNC1999 significantly inhibited the growth of the cells compared to the specific inhibitor of EZH2, GSK126. Interestingly, we found that concurrent loss of Utx and the activating Braf V600E mutation conferred resistance to proteasome inhibitors. Next, we compared the dual inhibition of EZH2 and EZH1 with the specific inhibition of EZH2 as partners of proteasome inhibitors using UNC1999 and GSK126, respectively. Our results showed that UNC1999 exhibited stronger synergistic effects than GSK126 as evidenced by the combination index. This suggests that UNC1999 enhances bortezomib-induced cytotoxicity by blocking residual PRC2 activity through inhibition of EZH1.
Next, I used doxycycline-inducible lentiviral vectors to overexpress wild type-UTX in our Utx -/- Braf V600E murine cell line. I found that UTX overexpression caused significant inhibition of the growth of the cells compared with control cells. However, I found no difference in the susceptibility to the specific EZH2 inhibitor GSK126, the dual inhibitor of EZH2 and EZH1 UNC1999 or the proteasome inhibitor bortezomib between the control and UTX overexpressing cells.
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| Research Progress Status |
翌年度、交付申請を辞退するため、記入しない。
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| Strategy for Future Research Activity |
翌年度、交付申請を辞退するため、記入しない。
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