Constitutive Expression of AID Leads to Tumorigenesis

Abstract

Genome stability is regulated by the balance between efficiencies of the repair machinery and genetic alterations such as mutations and chromosomal rearrangements. It has been postulated that deregulation of class switch recombination (CSR) and somatic hypermutation (SHM), which modify the immunoglobulin (Ig) genes in activated B cells, may be responsible for aberrant chromosomal translocations and mutations of non-Ig genes that lead to lymphocyte malignancy. However, the molecular basis for these genetic instabilities is not clearly understood. Activation-induced cytidine deaminase (AID) is shown to be essential and sufficient to induce both CSR and SHM in artificial substrates in fibroblasts as well as B cells. Here we show that constitutive and ubiquitous expression of AID in transgenic mice caused both T cell lymphomas and dysgenetic lesions of epithelium of respiratory bronchioles (micro-adenomas) in all individual mice. Point mutations, but not translocations, were massively introduced in expressed T cell receptor (TCR) and c-myc genes in T lymphoma cells. The results indicate that AID can mutate non-Ig genes including oncogenes, implying that aberrant AID expression could be a cause of human malignancy.

A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations

“…Most mice were viable at 90 weeks (Figure 1c), whereas in our earlier study, most AID transgenic mice died because of the lethal lymphoid malignancies, majority of which died within 50 weeks (Okazaki et al, 2003). Although TNAP is expressed in primordial germ cells, we did not observe any incidence of testicular or ovarian tumours in TNAP-AID mice.…”

“…Unfortunately, we could not carry out mutation analyses on the lung cancer tissue because of its small size. We did not examine microscopic tumours except for subpleural lung microadenomas, which were observed in the TNAP-AID mice, a finding similar to that in the AID transgenic mice in our earlier study (Okazaki et al, 2003). In addition, two cases of gastric adenocarcinoma were found incidentally by microscopic examination (Figure 2c), suggesting that many microscopic tumours may have been overlooked.…”

“…It hypothesizes that at least some cancer-related mutations are introduced by activation-induced cytidine deaminase (AID), an enzyme that is expressed in activated B lymphocytes, and is required for somatic hypermutation (SHM) and class-switch recombination of antibody genes (Honjo et al, 2002). The hypothesis is based on the following observations: (1) AID can induce mutations in non-B cells (Yoshikawa et al, 2002); (2) AID transgenic mice develop various tumours, including T-cell lymphoma and lung microadenoma (Okazaki et al, 2003) and (3) AID can be induced in human hepatic, gastric and biliary epithelial cells when stimulated with pro-inflammatory cytokines, such as transforming growth factor-b and tumor necrosis factor-a, and when challenged with pathogens, such as hepatitis C virus (HCV) and Helicobacter pylori. AID is detected in the liver, stomach and bile duct in humans (Kou et al, 2006;Endo et al, 2007;Matsumoto et al, 2007;Komori et al, 2008).…”

“…However, we have found earlier that it is difficult to analyse epithelial tumours of tissues other than lymphoid malignancies in a transgenic mouse model with constitutive and ubiquitous AID expression because of early death of the mice from lethal T-cell lymphoma (Okazaki et al, 2003).…”

Active nuclear import and cytoplasmic retention of activation-induced deaminase

“…All the known components in these pathways except for AID are ubiquitous DNA repair enzymes (reviewed in [3][4][5] ). Indeed, AID is able to trigger SHM and CSR in non-B cell models 6,7 and since such mutagenic and recombinogenic enzyme is potentially dangerous, it needs to be tightly regulated. This is highlighted by the cancer predisposition phenotype observed in transgenic mice overexpressing AID 7 , by the finding that ectopic SHM can occur in proto-oncogenes and tumor suppressor genes [8][9][10] and by the involvement of AID in oncogenic chromosomal translocations 11,12 .…”