| Project/Area Number |
13470204
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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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| Research Field |
Hematology
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| Research Institution | Kyoto University |
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Principal Investigator |
IMADA Kasunori (2002-2003) Kyoto University, Graduate School of Medicine, Assistant Professor, 医学研究科, 助手 (20314213)
大野 仁嗣 (2001) 京都大学, 医学研究科, 助教授 (40263082)
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| Co-Investigator(Kenkyū-buntansha) |
今田 和典 京都大学, 医学研究科, 助手 (20314213)
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| Project Period (FY) |
2001 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥13,600,000 (Direct Cost: ¥13,600,000)
Fiscal Year 2003: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2002: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2001: ¥8,800,000 (Direct Cost: ¥8,800,000)
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| Keywords | B-cell lymphoma / BCL6 gene / t(3;6)(q27;p21) / Histone H4 gene / H4 / BCL6 fusion gene / t(3;16)(q27;p11) / IL-21 receptor gene / transgenic mouse / somatic hypermutation / 遺伝子発現プロフィル / Real-time PCR / IL-21R遺伝子 / びまん性大細胞型リンパ腫 / プロモーター / IL-21R / BCL6融合mRNA / COS7細胞 / 胚中心 |
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| Research Abstract |
A recurrent translocation, t(3;6)(q27;p21), in B-cell non-Hodgkin's lymphoma results in fusion of BCL6 with a particular histone H4 gene on 6p21. We cloned five H4/BCL6 junctions and found somatic mutations of histone H4 and BCL6 genes within the regions involve in t(3;6)(q27;p21). Thus, the somatic hypermutation mechanism is likely to target H4, resulting in a predisposition to the development of translocation with BCL6. We constructed expression plasmids that mimicked the H4/BCL6 fusion gene. Many genes were underexpressed in the H4/BCL6-transfected cells as compared with the normal BCL6-transfected cells. This observation is in agreement with the fact that Bcl-6 acts as a transcriptional repressor. H4/BCL6-transfected cells expressed markedly higher levels of Bel-6 protein than normal BCL6-transfected cells. These data provided evidence that t(3;6) can promote Bcl-6 expression, which leads to significant alteration of the gene expression profile of t(3;6)-carriying cells. Next, we generated several transgenic mice carrying the H4/BCL6 fusion gene. However, the expression of transgene was not detected. We are new modifying the promoter region of the H4/BCL6 construct. We also found that the gene for interleukin-21 receptor (IL-21R) is the partner of BCL6 in t(3;16)(q27;p11) translocation, which is recurrently observed in B-cell lymphoma. COS-7 cells transiently transfected with the IL-21R/BCL6 fusion gene expressed high level Bcl-6 protein, indicating that expression of BCL6 can be enhanced by t(3;16). In addition, B-cell lymphoma and adult T-cell leukemia (ATL) cells were found to express IL-21R through the screening of various lymphoid malignancies, suggesting that the partner gene of BCL translocation is also involved in lymphomagenesis.
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