Oncogenic events triggered by AID, the adverse effect of antibody diversification

Abstract

The generation of an efficient immune response depends on highly refined mechanisms of antibody diversification. Two of these mechanisms, somatic hypermutation (SHM) and class switch recombination (CSR), are initiated by activation-induced cytidine deaminase (AID) upon antigen stimulation of mature B cells. AID deaminates cytosines on the DNA of Ig genes thereby generating a lesion that can be processed into a mutation (SHM) or a DNA double-strand break followed by a recombination reaction (CSR). A number of mechanisms are probably responsible for regulating AID function, such as transcriptional regulation, subcellular localization, post-transcriptional modifications and target specificity, but the issue remains of how unwanted DNA damage is fully prevented. Most lymphocyte neoplasias are originated from mature B cells and harbour hallmark chromosome translocations of lymphomagenic potential, such as the c-myc/IgH translocations found in Burkitt lymphomas. It has been recently shown that such translocations are initiated by AID and that ataxia-telangiectasia mutated, p53 and ARF provide surveillance mechanisms to prevent these aberrations. In addition, evidence is accumulating that AID expression can be induced in B cells independently of the germinal centre environment, such as in response to some viral infections, and occasionally in non-B cells, at least in certain inflammation-associated neoplasic situations. The most recent findings on AID expression and function and their relevance to the generation of oncogenic lesions will be discussed.

Somatic hypermutation analysis in follicular lymphoma provides evidence suggesting bidirectional cell migration between lymph node and bone marrow during disease progression and relapse

“…17,[31][32][33] Our conclusion that FL originates in the LN is consistent with the hypothesis of a possible dormant FL tumor stem cell harboring an unmutated, rearranged IgV H/L gene as part of the t(14;18)(q32;q21) translocation, which is possibly exposed to the somatic hypermutation machinery by passing the germinal centers of LN, acquiring additional point mutations and progressing to clinically overt FL. 34,35 In the FL population of the first patient, we detected a putative naïve LN clone with an unmutated IgV H gene and consequently identified it as the founder clone of this FL. Unfortunately, no further naïve founder clones were found in this study, but clones with few mutations were detectable in patients 2 and 3.…”

Genetics of Chronic Lymphocytic Leukemia: Practical Aspects and Prognostic Significance

“…Although representing different processes, SHM and CSR are both initiated by AID (Gostissa et al, 2011;Perez-Duran et al, 2007). SHM generates point mutations, small deletions and insertions in variable region exons.…”

“…The generated lesion can be processed into a mutation (SHM) or a DSB followed by a recombination reaction (CSR) (Perez-Duran et al, 2007). CSR requires the generation of AIDinitiated DSBs.…”

“…The latter are only occasionally generated as by-products of AID activity (Gostissa et al, 2011). It has been suggested that AID may have a dual role; initiating chromosomal translocations on one hand and generating secondary hits by mutagenesis on the other (Perez-Duran et al, 2007). Aberrant SHM and involvement of AID were reported to be involved in mutations of TP53 (Malcikova et al, 2008), MYC, PAX5 and RhoH (Reiniger et al, 2006).…”

“…Moreover, AID activity has been linked to the generation of DSBs involved in translocations in both IG and non-IG loci (Gostissa et al, 2011). While AID was shown to initiate the formation of translocations and mutations, ATM, p53 and ARF provide surveillance mechanisms to prevent these aberrations (Perez-Duran et al, 2007).…”