Expression of the AID protein in normal and neoplastic B cells

Abstract

IntroductionSomatic hypermutation (SHM) is a specialized process that takes place in germinal center (GC) B cells in response to T celldependent antigen stimulation. 1,2 This process introduces single nucleotide substitutions, with occasional deletions and duplications, primarily into the variable region of the immunoglobulin (IgV) heavy and light chain genes, resulting in the production of high-affinity antibodies and allowing affinity maturation of the humoral immune response. 3 SHM requires active transcription of the target locus but is not IgV sequence specific and does not depend on the V region promoter. [4][5][6][7] In fact, at least 3 non-Ig genes, including BCL6, the FAS/CD95 gene, and the genes encoding the 2 components of the BCR (B29 and mb1) have been shown to acquire somatic mutations during the normal GC reaction, indicating that this mechanism may target more genes than originally suspected. [8][9][10][11][12] The molecular basis of SHM remains largely unknown. However, studies from the past 4 years have identified the AID gene, encoding for activation-induced cytidine deaminase, as an absolute requirement for both SHM and class switch recombination (CSR) in humans and mice. 13,14 Activation-induced cytidine deaminase (AID) expression is also sufficient to initiate both events in fibroblasts expressing transcribed artificial constructs. 15,16 Because of the high homology with the RNA-editing enzyme apolipoprotein B editing catalytic subunit 1 (APOBEC-1), it has been proposed that AID may function as a cytidine deaminase to modify a preexisting mRNA into a new one, possibly encoding an endonuclease. 14,17 However, experimental evidence in Escherichia coli indicated that AID may act directly on DNA and convert deoxycytidines to uracils, which are then processed by uracil-DNA glycosylase (UNG) and endonucleases. 18 AID would thereby lead to the creation of abasic sites, which may be repaired by base excision repair and putative error-prone mechanisms. Indeed, in vitro AID exhibits cytidine deamination activity on single-stranded DNA, with a base specificity similar to that reported for SHM. [19][20][21][22] Recently, the SHM process has been shown to malfunction in about 50% of diffuse large B-cell lymphomas (DLBCLs) as well as in about 20% of AIDS-related non-Hodgkin lymphomas (NHLs) and in a significant fraction of primary central nervous system lymphomas derived from non-HIV patients. [23][24][25] In these tumors, multiple somatic mutations are introduced into the 5Ј region, including coding sequences, of several genes that do not represent physiologic SHM targets. These comprise the well-known protooncogenes PIM1, PAX5, RhoH/TTF, and cMYC, all of which have Two of the authors (R.P. and J.M.) are employed by a company (Cell Signaling Technology, Inc, Beverly, MA) whose potential product was studied in the present work.The online version of this article contains a data supplement.An Inside Blood analysis of this article appears in the front of this issue.Reprints: Laura Pasqualucci, Institute for...

Duodenal and nodal follicular lymphomas are distinct: the former lacks activation-induced cytidine deaminase and follicular dendritic cells despite ongoing somatic hypermutations

“…This sounds contradictory; however, Bombardieri et al 25 reported that neoplastic marginal zone-like B cells are AID-negative but have somatic and ongoing mutations. 26 On the other hand, Smit et al, 27 Pasqualucci et al 28 and Lossos et al 9 reported of lack of correlation between AID expression and intraclonal diversity of VH genes in B-cell non-Hodgkin's lymphomas. And Smit et al 27 mentioned that AID expression at follicular lymphomas were 25%, and intraclonal variation was found in the absence of AID, but they did not explained histology, immunophenotype and stage.…”

Oncogenic Mechanisms in Burkitt Lymphoma

“…One important aspect of this GC program is AID, which mediates somatic hypermutation and IG CSR in normal GC cells but in experimental settings can also induce IG/MYC translocations similar to those found in BL (Pasqualucci et al 2004;Ramiro et al 2004). GC-restricted transcription factors can have a powerful oncogenic effect when dysregulated because they can simultaneously affect multiple downstream pathways.…”

Active nuclear import and cytoplasmic retention of activation-induced deaminase

“…The difference with AID-GFP, which accumulates in the nucleus of Ramos, could be explained by a combination of overexpression and the C-terminal tag weakening retention, just as an N-terminal tag affects import. AID is vastly confined to the cytoplasm of germinal center B cells 48,[53][54][55] . Only a very small proportion of the B cells in rabbit appendix 48 and human tonsils 53 , and hardly any cell in unsynchronized populations overexpressing AID-GFP, seem to contain predominantly nuclear AID.…”