Activation-induced deaminase as a mutator oncogene

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DESCRIPTION (provided by applicant): Activation induced deaminase (AID) is expressed in normal activated B-lymphocytes, where it is required for immunoglobulin (Ig) gene somatic hypermutation (SHM) and class switch recombination (CSR). While AID bears significant similarity to the RNA editing enzyme APOBEC-1, recent findings suggest that it may act directly on DNA, changing cytidine residues into uridine. This application is based on the hypothesis that loss of regulation of AID activity results in somatic hypermutation affecting the entire genome, instead of being highly targeted to Ig genes. As such, deregulated AID could act as a mutator oncogene, contributing to neoplastic development and progression, specifically in B cell malignancies. In support of this model is the finding that AID is constitutively expressed in many human B cell leukemias and lymphomas, although in these samples AID expression is often uncoupled from active SHM of Ig genes, suggesting functional deregulation. Significantly, alternatively spliced AID mRNAs, capable of encoding truncated AID isoforms lacking regions that are thought to be involved in substrate targeting, are reproducibly found in B cell neoplastic samples. Finally, ubiquitous AID overexpression in transgenic mice results in T cell lymphomas, but - surprisingly - not B cell neoplasias. A gain-of-function mutator phenotype as the one hypothesized here would represent a novel pathogenetic mechanism, and would suggest that AID may be a useful target for pharmacological intervention to curtail neoplastic progression. In this respect, several known and likely inhibitors of cytidine deaminases have already been characterized, and could find rapid clinical application. Based on structural and functional studies, we predict that truncated AID isoforms will display altered targeting patterns, or dominantly disrupt targeting of wild-type AID. We propose to specifically test the potential effects of truncated AID isoforms on SHM activity is indeed deregulated in malignant B cells, and to investigate the effect of expression of truncated AID isoforms on SHM and CSR activity. To formally prove the causal involvement of AID in B cell malignancy we will generate new transgenic mice in which AID expression will recapitulate the pattern observed in some diffuse large B cell lymphomas. Finally, we will test a series of drug candidates for their ability to suppress AID cytidine deaminase activity as a prelude to future targeted pharmacological interventions.