We have shown that mice constitutively expressing AID succumbed to T cell lymphomas. Furthermore, the mice developed micro-adenomas and adenocarcinomas in lung. Strikingly, point mutations but not translocations were massively introduced in the rearranged and expressed TCR
genes as well as in the c-myc
proto-oncogene with similar distribution and base specificity to those observed in B cells (2
), B lymphomas (4
), and AID-overexpressing cells in vitro (9
). Although a recent study showed that multiple proto-oncogenes are hypermutated in DLCLs (4
) which are derived from GC B cells and express AID, whether these SHM-like mutations and expression of AID are responsible to or resultant from lymphomagenesis is unclear since most tumor cells are genetically unstable (20
). However, our findings indicate that deregulated or ectopic expression of AID contributes to tumorigenesis by introducing mutations in non-Ig genes rather than generating chromosomal translocations. This is the first report of tumorigenesis by a gene product that can act as a direct, potent mutator, but not by breakdown of systems that ensure the genome stability.
The marked reduction of life spans in progenies of the B2 line, which originally showed slower onset of diseases, implies that mutations affecting tumor susceptibility accumulated in germ cells. Since generation transfer of Tg mice were mediated by three males and all Tg progenies of the same generation showed similar phenotypes, the number of mutation targets that are probably involved in tumor susceptibility or life spans may be very large. The accumulation of mutations in oncogenes or tumor-suppressor genes are thought to result in tumorigenesis (20
). The genome instability is observed at both nucleotide and chromosomal levels. Defects in the repair systems such as nucleotide-excision repair and mismatch repair (MMR) systems are involved in subtle sequence instabilities, while defects in the checkpoint machinery such as mitotic spindle checkpoint and DNA-damage checkpoint systems are involved in chromosomal instabilities including gains and losses of whole chromosomes and chromosomal translocations (20
). Curiously, mice lacking genes involved in either the MMR system (Msh2
]) or the checkpoint machinery (p53
], and Brca2
]) develop T cell lymphomas almost exclusively or preferentially. Such exclusive occurrence of T cell lymphomas was also observed in AID Tg mice. The reason why other types of tumors than T lymphomas were rarely observed in AID Tg mice may be simply because T lymphoma cells take off and expand well in advance of generation of tumors in other cells. Although the reason why no B cell lymphoma developed is also unclear, it is possible that B cells have a protective system to prevent excessive activity of AID, making the onset of B lymphomagenesis slower than that of T lymphomagenesis. However, many types of tumors might potentially occur because in AID Tg mice mutations were introduced in the c-myc
and probably other proto-oncogenes.
AID shows homology to apolipoprotein B mRNA editing catalytic subunit 1, APOBEC-1, a member of RNA-editing cytidine deaminase family (5
). Tumorigenesis in AID Tg mice is reminiscent of development of hepatocellular carcinomas in mice ectopically expressing APOBEC-1 in liver (28
). Other hepatic mRNAs involved in cell growth and regulation than apo-B mRNA were aberrantly edited in APOBEC-1 Tg mice (28
). As the apo-B gene in Tg livers was not mutated (28
), the mechanism for tumorigenesis in APOBEC-1 Tg mice may be attributed to aberrant editing of mRNAs, but not to direct action on DNA. On the contrary, non-Ig genes including the c-myc
proto-oncogene were mutated in AID Tg mice in a similar way to the Ig gene, although whether AID acts on RNA or DNA is still controversial (1
As constitutive expression of AID causes tumorigenesis, expression of AID has to be tightly regulated in normal mice. Otherwise, deregulatedly or ectopically expressed AID will cause enormous genomic instability. Thus, ectopic expression of AID could be partly responsible to malignancy in mouse as well as human. It is important to screen whether AID is ectopically expressed in human cancers of non-B cell origins. In addition, AID Tg mice might be a better model system to screen tumor-suppressor genes, as mutations in AID Tg mice are restricted to transcribed genes and accumulate through generations.