| Budget Amount *help |
¥3,890,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
As disease models for human malignancies, a number of gene-engineered mice, including transgenic and knockin mice, have been generated. However, these mice fundamentally differ from human diseases in several points: firstly, in the transgenic and knockin system, every cell contains the transgene and there exist no normal cells, in contrast that human disease originated from acquiredly transformed cells. Secondly, in the transgenic and knockin system, since the transgene-derived product is congenitally expressed, there is no elimination of transgene-expressing cells by the immune system, in contrast that in human diseases, most of the transformed cells would be ablated by the immune-bearing cells and those escaped from this system expand and finally exhibit malignancies. To overcome this issue and to create a mouse model further mimicking human disease, we attempted to generate and analyze novel model mice that acquiredly express mutated genes. We chose E2A/HLF fusion gene as a target g
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ene, which was found in acute lymphoblastic leukemia, and utilized conditional knockin system using Cre/loxP system. Interestingly, although the resultant mice acquiredly expressed E2A/HLF in the hematopoietic tissues, they did not show any hematological disease, indicating that acquired expression of E2A/HLF alone is not sufficient to develop leukemia. To investigate whether a second hit is necessary to induce a fully malignant phenotype, we employed "retrovirus-tagged in vivo mutagenesis" to the mice, which has successfully been used to activate or inactivate endogenous genes by random integration into the mouse genome. As a result, virus-infected E2A/HLF conditional knockin mice developed leukemia, and we isolated three transcription factors, including Gfi1 (growth factor independence 1), Ikaros, and Evi3 as virus target genes. These results first demonstrated that E2A/HLF cooperates with a specific set of transcription factors to develop leukemia. Further studies will be required to investigate the underlying mechanism of how E2A/HLF cooperates with these genes to induce a fully malignant phenotype. Less
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