| Project/Area Number |
22K16318
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 54010:Hematology and medical oncology-related
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Rizq Ola 東京大学, 医科学研究所, 特任研究員 (60823698)
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| Project Period (FY) |
2022-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2023: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2022: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | myeloma / UTX / Braf V600E / epigenetics / mature B cells / mouse model / Epigenetics / BRAF V600E / KDM6A / Myeloma / tumor suppressor |
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| Outline of Research at the Start |
In this study, I will examine the biological role of UTX in MM using a mouse model in which Utx is conditionally deleted in germinal center (GC), post-GC B cells and plasma cells. In addition, I will investigate the cooperation between Utx loss and the activating Braf V600E mutation in our mouse model. The proposed study will shed light on how the dysfunction of epigenetic modifiers contributes to the pathogenesis of MM.
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| Outline of Final Research Achievements |
UTX, an X-linked histone demethylase, is inactivated/deleted in 1.5-4% of multiple myeloma (MM) patients. We established a novel myeloma mouse model in which Utx loss and Braf V600E mutation are combined. We observed a significantly shortened survival of compound mice compared to Cre negative control, single Utx loss or single Braf V600E KI. Add-back of WT or mutant UTX revealed that the cIDR domain is largely responsible for the tumor suppressor function of UTX while its demethylase activity is dispensable. Analysis of our RNA seq data from BM plasma cells from MM mice showed moderate transcriptomic reprogramming of plasma cells towards a myeloma-like transcriptome after a long latency. Our Utx/Braf mutant cells had largely different chromatin accessibility and H3K27ac status from control plasma cells. These data suggest that epigenomic reprogramming gradually proceeds in the absence of UTX and/or plasma cell clones that acquire myeloma-like properties are selected over time.
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| Academic Significance and Societal Importance of the Research Achievements |
We developed a mouse model in which Utx loss and the activating Braf V600E mutation induced mature B-cell malignancies including multiple myeloma. We found that epigenomic reprogramming gradually proceeded and/or plasma cell clones that aquired myeloma-like properties were selected over time.
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