AID overexpression leads to aggressive murine CLL and non-Ig mutations that mirror human neoplasms

Most cancers become more dangerous by the outgrowth of malignant subclones
with additional DNA mutations that favor proliferation or survival. Using
chronic lymphocytic leukemia (CLL), a disease exemplary of this process,
and a model for neoplasms in general, we created transgenic mice
overexpressing the enzyme, activation-induced deaminase (AID), whose
normal function is to induce DNA mutations in B lymphocytes. AID allows
normal B lymphocytes to develop more effective immunoglobulin
(Ig)-mediated immunity, but also is able to mutate non-Ig genes,
predisposing to cancer. In chronic lymphocytic leukemia (CLL), AID
expression correlates with poor prognosis suggesting a role for this
enzyme in disease progression. Nevertheless, direct experimental evidence
identifying the specific genes that are mutated by AID and indicating that
those genes are associated with disease progression is not available. To
address this point, we overexpressed Aicda in a murine model of CLL
(Em-TCL1). Analyses of TCL1/AID mice demonstrate a role for AID in disease
kinetics, CLL-cell proliferation, and the development of cancer-related
target mutations with canonical AID signatures in non-Igs genes. Notably,
our mouse models can accumulate mutations in the same genes that are
mutated in human cancers. Moreover, some of these mutations occur at
homologous positions, leading to identical or chemically-similar amino
acid substitutions as in human CLL and lymphoma. Together, these findings
support a direct link between aberrant AID activity and CLL driver
mutations that are then selected for their oncogenic effects, whereby AID
promotes aggressiveness in CLL and other B-cell neoplasms.