Research of novel treatment for childhood leukemia by disrupting the chimeric gene function using RNAi

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Chromosome translocations are one of the genomic mutations which are responsible for childhood leukemia and other malignant disorders. Because chromosome translocation generates chimeric mRNA which promote the carcinogenesis, the disruption of chimeric mRNA function using RNAi is thought to be possible therapeutic approach for childhood leukemia and malignant disorders. However, genomic structure of translocation breakpoint have not been clarified in some cases, which hampers the development of novel therapy using RNAi. In this Research, to establish this new therapeutic strategy, the molecular structure of chimeric mRNA generated by chromosomal translocation was analyzed.We analyzed the translocation breakpoint of acute myelocytic leukemia (AML) cells with t(15;17)(q13;q11), and synovial sarcoma cells with t(2;2)(q21;q35). A cDNA library derived from AML cells were established and bacteriophages containing translocation breakpoint have been selected. In the case of synovial sarcoma cells, because PAX3 gene which is common breakpoint of rhabdomyosarcoma is located on the one site of breakpoints, counterpart have been analyzed using 3'-RACE (rapid amplification of cDNA end) method. Candiate product containing chimeric mRNA have been amplified.These results promote the novel therapeutic strategy disrupting chimeric mRNA using RNAi. The effect of RNAi which disrupt these chimeric mRNA will be analyzed.