In addition, through off-target activity, AID has a much broader effect on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in the development and progression of lymphoma.
We examined expression levels of the AID gene in 89 lymph node specimens from lymphoma and non-lymphoma patients with Northern blot analysis and investigated an association with their survival.
Activation-induced cytidine deaminase (AID), the enzyme responsible for induction of sequence variation in immunoglobulins (Igs) during the process of somatic hypermutation (SHM) and also Ig class switching, can have a potent mutator phenotype in the development of lymphoma.
In line with this, we found that clustered mutations (kataegis) in lymphoma and chronic lymphocytic leukemia predominantly carry AID-hotspot mutational signatures.
Accordingly, BCL2 mutations can affect antiapoptotic Bcl-2 function, are associated with increased activation-induced cytidine deaminase expression, and correlate with increased risk of transformation and death due to lymphoma.
Additional work is needed to further define the full scope and consequences of off-target AID activity in human lymphoma as well as to understand the protective mechanisms that break down during the development and progression of disease.
Although AID was first thought to be Ig-specific, recent work indicates that it also targets a diverse group of non-Ig loci, including genes such as Bcl6 and c-myc, whose modification by AID results in lymphoma-associated mutations and translocations.
Activation-induced cytidine deaminase expression in diffuse large B-cell lymphoma with a paracortical growth pattern: a lymphoma of possible interfollicular large B-cell origin.
In addition, experiments with AID-deficient mice clearly showed that AID is required not only for the c-myc/IgH translocation but also for the malignant progression of translocation-bearing lymphoma precursor cells, probably by introducing additional genetic hits.
It is unclear whether intraclonal V gene diversification by somatic hypermutation, which is strictly dependent on the enzyme activation induced cytidine deaminase (AID), is restricted to the early phase of lymphoma clone expansion and later silenced, or whether it remains active throughout malignant proliferation.