Over the past decade the genetics of development and cancer have converged with the identification of signaling pathways that control embryo patterning and, when aberrantly regulated, lead to cancer. A classic example is the canonical Wnt/beta-catenin signaling pathway, an essential developmental pathway that is misregulated in several different cancers. Mutations in oncogenes or tumor suppressors identified in this pathway lead to its constitutive activation. Alternative Wnt signaling pathways, stimulated by Wnt5a, have been shown to antagonize Wnt/beta-catenin signaling suggesting that these pathways could function to suppress tumorigenesis. ? ? We have discovered that mutations that affect alternative Wnt signaling pathways can enhance cancers of the immune system. We have shown that acute T cell lymphocytic leukemia developed in adult mice lacking the tumor suppressor Tcf1. Loss of Tcf1 repressor activity led to the upregulation of select Wnt/?catenin target genes such as c-myc and Lef1 in thymocytes. Removal of one copy of Wnt5a on this Tcf1 mutant background enhanced the frequency and onset of lymphoma through a mechanism that does not require loss of heterozygosity. Thus Wnt5a appears to function as a haploinsufficient tumor suppressor. Despite the elevated levels of Lef1 and other Wnt target genes observed in the compound mutant tumors, we did not detect elevated, or ectopic, expression in vivo of beta-catenin or a Wnt/bcatenin reporter in the thymus or in embryos lacking Wnt5a and Tcf1. Our results suggest that Tcf1 and Wnt5a function as interactive tumor suppressors to repress genes that are not regulated by Wnt/bcatenin signaling alone. A manuscript describing this work has been written and will be submitted shortly.? ? Our current experiments are aimed at understanding the underlying mechanisms of tumor suppression by Wnt5a and Tcf1. In the last year we have completed a microarray project to generate transcriptional profiles of tumors so that we can molecularly compare our lymphomas with clinically and molecularly classified human lymphomas. Furthermore, we are interested in identifying target genes of this tumor suppressor pathway. We have identified several genes that are very good candidates and have validated the microarray data for these genes by RT-PCR. One of these target genes, Runx1, has been previously shown by retroviral insertional screens to be activated in lymphomas. We have found that Runx1 up-regulation is only associated with Wnt5a mutations suggesting that Runx1 may be a Wnt5a target gene. We are currently addressing this hypothesis, as well as continuing to validate other candidate target genes by examining their expression in vivo using tissue collected from wildtype and targeted mutants. Functional analysis of candidate oncogenes will be initially assessed in vitro in cell proliferation and transformation assays and by RNAi. Our experiments should provide insights into the molecular mechanisms underlying lymphomagenesis. ?
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