Mouse models of human chromosomal translocations and approaches to cancer therapy

Cancer arises because of genetic changes in somatic cells, eventually givin g rise to overt malignancy. Principle among genetic changes found in tumor cells are chromosomal translocations which give rise to fusion genes or enf orced oncogene expression. These mutations are tumor-specific and result in production of tumor-specific mRNAs and proteins and are attractive targets for therapy. Also, in acute leukemias, many of these molecules are transcr iption regulators which involve cell-type-specific complexes, offering an a lternative therapy via interfering with protein-protein interaction. We are studying these various features of tumor cells to evaluate new therapeutic methods. We describe a mouse model of de novo chromosomal translocations u sing the Cre-loxP system in which interchromosomal recombination occurs bet ween the MII and Af9 genes. We are also developing other in vivo methods de signed, like the Cre-loxP system, to emulate the effects of these chromosom al abnormalities in human tumors. In addition, we describe new technologies to facilitate the intracellular targeting of fusion mRNAs and proteins res ulting from such chromosomal translocations. These include a masked antisen se RNA method with the ability to discriminate between closely related RNA targets and the selection and use of intracellular antibodies to bind to ta rget proteins in vivo and cause cell death. These approaches should also be adaptable to targeting point mutations or to differentially expressed tumo r-associated proteins. We hope to develop therapeutic approaches for use in cancer therapy after testing their efficacy in our mouse models of human c ancer, (C) 2001 Academic Press.