Mutator Genes UDG and AID Appear To Be Normal in Class-Switch Deficient and Clonally Homogeneous Waldenstrom’s Macroglobulinemias Having Either Germline or Hypermutated Clonotypic IgH VDJ.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1359-1359
Author(s):  
Jitra Kriangkum ◽  
Brian J. Taylor ◽  
Erin R. Strachan ◽  
Steven P. Treon ◽  
Michael J. Mant ◽  
...  
Keyword(s):  
B Cells ◽  
Somatic Hypermutation ◽  
Splice Variants ◽  
Cytidine Deaminase ◽  
Essential Elements ◽  
Class Switching ◽  
Conserved Sequence ◽  
Class Switch ◽  
Mutator Genes

Abstract Clonotypic B cells of Waldenstrom’s macroglobulinemia (WM) are characterized as CD20+IgM+IgD+ cells that are usually somatically mutated in IgH VDJ but for some patients, the clonotypic IgH VDJ is germline (unmutated).For both mutated and unmutated clones, WM lack ongoing somatic hypermutation (SHM) and class switch recombination (CSR). This may be due to abnormalities in switching and/or mutator genes. To understand the nature of unswitched tumor B cells, uracil DNA glycosylase (UDG) and activation-induced cytidine deaminase (AID), the two essential elements for CSR, were analysed in WM. Analysis of 12 WM clones characterized by somatic hypermutation showed that the mutation profile of VH genes had normal transition/transversion ratios at C or G, and thus did not suggest UDG abnormalities. Expression of AID was determined by single stage RT-PCR. Out of 14 patients studied (2 unmutated and 12 mutated VH clones), two of them (WM1-01 and WM1-08,with mutation rates of 0% and 6.2% respectively) gave positive bands. In WM1-01, despite having a germline IgH VDJ, AID is consistently expressed in two bone marrow samples collected three years apart and from which the identical unmutated clonotypic VDJ sequence was isolated. Full-length (FL) AID transcripts of WM have a conserved sequence, thus ruling out the possibility of functional defects due to point mutation. In addition, detection of AID in an unmutated VH clone suggested that lack of SHM does not result from an inability to produce AID. In addition to FL transcripts, three other splice variants were identified in both patients. Single cell analysis indicated that only a small compartment (10% or less), not all, of clonotypic B cells expressed AID, and multiple isoforms may be detectable in individual cells. Whether these splice variants that contain truncated C-terminal ends play a role in the regulation of CSR in WM remains to be investigated. Splice variants, nevertheless, may not characterize tumor B cells since up to 10% of AID-expressing normal activated B cells (n=3) also carried them. In vitro activation of clonotypic WM B cells by CD40L and IL4, using conditions that induced CSR in normal B cells, did not yield detectable class switching in WM B cells. In cultures of B cells from WM, the number of non-clonal B cells increased but the clonotypic B cells did not appear to expand, as indicated by the reduction of clonotypic IgM transcript at 5-days of culture. Thus, as well as failing to undergo somatic mutation or class switching, WM tumor B cells appear unresponsive to CD40L+IL4. They may be fundamentally unresponsive to signals for class switching and their clonal expansion may depend upon alternate signaling pathways.

Mucosal Epithelial Cells Initiate Frontline Immunoglobulin Class Switching through an SLPI-Regulated Pathway.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3898-3898
Author(s):  
Andrea Cerutti ◽  
Bing He ◽  
April Chiu ◽  
Meimei Shan ◽  
Paul Santini ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
B Cells ◽  
Epithelial Cells ◽  
B Cell ◽  
Antibody Production ◽  
Cytidine Deaminase ◽  
Dna Recombination ◽  
Class Switching ◽  
Class Switch

Abstract Introduction. Class switching from IgM to IgG and IgA is central to immunity against microbes and usually occurs in draining lymph nodes and requires activation of B cells by CD4+ T cells expressing CD40 ligand. Growing evidence indicates that B cells can mount frontline IgG and IgA responses at mucosal sites of entry through an alternative CD40-independent pathway involving B cell-activating factor of the TNF family (BAFF, also known as BLyS) and a proliferation-inducing ligand (APRIL). These innate factors are usually produced by dendritic cells and stimulate B cells through at least three distinct receptors. Together with dendritic cells, epithelial cells have a key position at the host-environment interface. Therefore, we asked whether epithelial cells play a role in frontline antibody production. Methods. Tonsillar tissue sections from healthy donors were analyzed for expression of activation-induced cytidine deaminase (AID) by immunohistochemistry and in situ hybridization. A simplified in vitro model reproducing the geometry of mucosal surfaces was used to evaluate the role of epithelial cells in class switching. Briefly, primary epithelial cells and B cells were cultured in the upper and lower chambers, respectively, of a trans-well system. Monocyte-derived dendritic cells were positioned on a filter separating the two chambers. Various microbial product analogues were used to mimic infection. RNA interference was performed to knockdown BAFF in epithelial cells. AID expression, CSR, antibody production and signaling were evaluated in B cells as reported (Litinsky et al., Nat. Immunol.2002, 3:822–829; Qiao et al., Nat. Immunol.2006, 7:302–310). Results. We found that the upper respiratory mucosa of healthy subjects comprised intraepithelial pockets filled with B cells expressing AID, a DNA-editing enzyme associated with ongoing class switch DNA recombination (CSR). Epithelial cells released innate class switch-inducing factors, including BAFF, after sensing microbial products through TLRs, thereby inducing AID expression, CSR, and ultimately IgG and IgA production in neighboring B cells. Epithelial cell-induced antibodies comprised polyreactive IgG and IgA capable of recognizing multiple microbial determinants. Intraepithelial class switching was enhanced by thymic stromal lymphopoietin (TSLP), an epithelial IL-7-like cytokine that augments the innate B cell-licensing functions of dendritic cells, and restrained by secretory leukocyte protease inhibitor (SLPI), an epithelial alarm antiprotease that suppresses AID expression in activated B cells. Conclusions. The present findings indicate that epithelial cells function as non-immune sentinels capable to autonomously orchestrate compartmentalized IgG and IgA responses at the interface between host and environment. This implies that mucosal vaccines should activate both epithelial and immune cells to elicit optimal antibody production.

scholarly journals AID from bony fish catalyzes class switch recombination

2005 ◽  
Vol 202 (6) ◽  
pp. 733-738 ◽  
Author(s):  
Vasco M. Barreto ◽  
Qiang Pan-Hammarstrom ◽  
Yaofeng Zhao ◽  
Lennart Hammarstrom ◽  
Ziva Misulovin ◽  
...  
Keyword(s):  
B Cells ◽  
Catalytic Domain ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Class Switch Recombination ◽  
Adaptive Immune System ◽  
Bony Fish ◽  
Class Switching ◽  
Class Switch ◽  
Switch Regions

Class switch recombination was the last of the lymphocyte-specific DNA modification reactions to appear in the evolution of the adaptive immune system. It is absent in cartilaginous and bony fish, and it is common to all tetrapods. Class switching is initiated by activation-induced cytidine deaminase (AID), an enzyme expressed in cartilaginous and bony fish that is also required for somatic hypermutation. Fish AID differs from orthologs found in tetrapods in several respects, including its catalytic domain and carboxy-terminal region, both of which are essential for the switching reaction. To determine whether evolution of class switch recombination required alterations in AID, we assayed AID from Japanese puffer and zebra fish for class-switching activity in mouse B cells. We find that fish AID catalyzes class switch recombination in mammalian B cells. Thus, AID had the potential to catalyze this reaction before the teleost and tetrapod lineages diverged, suggesting that the later appearance of a class-switching reaction was dependent on the evolution of switch regions and multiple constant regions in the IgH locus.

Activation-induced cytidine deaminase in chronic lymphocytic leukemia B cells: expression as multiple forms in a dynamic, variably sized fraction of the clone

Blood ◽  
2003 ◽  
Vol 102 (9) ◽  
pp. 3333-3339 ◽  
Author(s):  
Emilia Albesiano ◽  
Bradley T. Messmer ◽  
Rajendra N. Damle ◽  
Steven L. Allen ◽  
Kanti R. Rai ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Somatic Hypermutation ◽  
Splice Variants ◽  
Cytidine Deaminase ◽  
Prognostic Indicator ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Activation Induced Cytidine Deaminase

AbstractThe degree of somatic mutation of immunoglobulin variable (Ig V) region genes is an important prognostic indicator of clinical course and outcome in B-cell chronic lymphocytic leukemia (B-CLL), although the reason for this association remains unclear. Furthermore, some B-CLL cells continue to acquire Ig V gene mutations after the transforming event. Because activation-induced cytidine deaminase (AID) is an essential component of the canonical somatic hypermutation process in healthy B cells, its expression in B-CLL is potentially relevant to the disease. We detected full-length AID transcripts and 3 splice variants by conventional reverse transcription polymerase chain reaction (RT-PCR) in approximately 40% of the cases examined. More sensitive real-time quantitative PCR detected AID transcripts in virtually all B-CLL samples tested, although the range of transcript levels was very large between different cases and varied within individual cases over time. Limiting dilution assays revealed that AID expression was restricted to a small fraction of the leukemic cells in the blood. However, this small fraction is not unique in its ability to express AID, because in vitro stimulation of B-CLL cells with appropriate stimuli significantly increased the fraction of AID-expressing cells. These data suggest that AID-mediated DNA alterations may occur in a variably sized, minor subset of B-CLL cells at any given time.

Immunoglobulin class-switch recombination in mice devoid of any Sμ tandem repeat

Blood ◽  
2004 ◽  
Vol 103 (10) ◽  
pp. 3828-3836 ◽  
Author(s):  
Ahmed Amine Khamlichi ◽  
Florence Glaudet ◽  
Zeliha Oruc ◽  
Vincent Denis ◽  
Marc Le Bert ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Germ Line ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Class Switch Recombination ◽  
Class Switching ◽  
The Core ◽  
Class Switch ◽  
Severe Impairment

Abstract Immunoglobulin heavy-chain class-switch recombination (CSR) occurs between highly repetitive switch sequences located upstream of the constant region genes. However, the role of these sequences remains unclear. Mutant mice were generated in which most of the Iμ-Cμ intron was deleted, including all the repeats. Late B-cell development was characterized by a severe impairment, but not a complete block, in class switching to all isotypes despite normal germ line transcription. Sequence analysis of the Iμ-Cμ intron in in vitro activated–mutant splenocytes did not reveal any significant increase in activation-induced cytidine deaminase (AID)–induced somatic mutations. Analysis of switch junctions showed that, in the absence of any Sμ repeat, the Iμ exon was readily used as a substrate for CSR. In contrast to the sequence alterations downstream of the switch junctions, very few, if any, mutations were found upstream of the junction sites. Our data suggest that the core Eμ enhancer could be the boundary for CSR-associated somatic mutations. We propose that the core Eμ enhancer plays a central role in the temporal dissociation of somatic hypermutation from class switching.

scholarly journals Regulation of class switch recombination and somatic mutation by AID phosphorylation

2008 ◽  
Vol 205 (11) ◽  
pp. 2585-2594 ◽  
Author(s):  
Kevin M. McBride ◽  
Anna Gazumyan ◽  
Eileen M. Woo ◽  
Tanja A. Schwickert ◽  
Brian T. Chait ◽  
...  
Keyword(s):  
Somatic Mutation ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Point Mutations ◽  
Class Switch Recombination ◽  
Variable Region ◽  
Dna Breaks ◽  
Class Switching ◽  
Class Switch

Activation-induced cytidine deaminase (AID) is a mutator enzyme that initiates somatic mutation and class switch recombination in B lymphocytes by introducing uracil:guanine mismatches into DNA. Repair pathways process these mismatches to produce point mutations in the Ig variable region or double-stranded DNA breaks in the switch region DNA. However, AID can also produce off-target DNA damage, including mutations in oncogenes. Therefore, stringent regulation of AID is required for maintaining genomic stability during maturation of the antibody response. It has been proposed that AID phosphorylation at serine 38 (S38) regulates its activity, but this has not been tested in vivo. Using a combination of mass spectrometry and immunochemical approaches, we found that in addition to S38, AID is also phosphorylated at position threonine 140 (T140). Mutation of either S38 or T140 to alanine does not impact catalytic activity, but interferes with class switching and somatic hypermutation in vivo. This effect is particularly pronounced in haploinsufficient mice where AID levels are limited. Although S38 is equally important for both processes, T140 phosphorylation preferentially affects somatic mutation, suggesting that posttranslational modification might contribute to the choice between hypermutation and class switching.

High Expression of Activation-Induced Cytidine Deaminase and in Vivo Class Switch Recombination in Mantle Cell Lymphoma: Further Support for Antigen Involvement in Lymphomagenesis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1538-1538
Author(s):  
Aliki Xochelli ◽  
Fotini Marantidou ◽  
Evangelia Stalika ◽  
Lesley-Ann Sutton ◽  
Alba Navarro ◽  
...  
Keyword(s):  
Somatic Hypermutation ◽  
Splice Variants ◽  
Cytidine Deaminase ◽  
Gene Repertoire ◽  
Transcript Levels ◽  
Class Switch ◽  
Ighv Gene ◽  
Activation Induced Cytidine Deaminase ◽  
Mantle Cell

Abstract Abstract 1538 According to the WHO 2008 Classification, the cellular origin of mantle cell lymphoma (MCL) is traced to a peripheral B cell of the inner mantle zone, mostly of naïve pre-germinal center type. This notion, however, is seriously challenged by both the remarkable restrictions of the immunoglobulin gene repertoire in MCL and, furthermore, by the fact that the great majority of cases exhibit imprints of somatic hypermutation (SHM) in rearranged IGHV genes, ranging from (mostly) minimal to pronounced. These findings support an antigen-driven origin for MCL, at least for a substantial fraction of the entire cohort. Activation-induced cytidine deaminase (AID) is induced in B cells following contact with antigen and is critically implicated in both somatic hypermutation (SHM) and class switch recombination (CSR). Although the available information about AID expression and in vivo CSR in MCL is limited and contradictory, at least some MCL cases have been reported to express AID and undergo ongoing CSR. With this in mind, here we investigated AID-mRNA isoform expression and isotype switch events in a large series of MCL cases and explored possible associations with IGHV gene repertoire and SHM status. Overall, 107 cases were included in the study and tumor-involved diagnostic tissue samples of different types were evaluated, including: fresh-frozen lymph nodes (LN, n=53), peripheral blood (PB, n=42), spleen (n=5), bone marrow biopsies (n=3) and other (n=4). The neoplastic lymphocytic infiltration ranged from 52–98% (median 80%). Thirty-five of 107 cases (32.7%) carried IGHV genes with 100% identity to the germline (GI) whereas the remaining 72 cases bore some imprint of SHM: in particular, 48/107 cases (44.9%) carried IGHV genes with 97–99.9% GI and, finally, 24/107 cases (22.4%) carried IGHV genes with <97% GI. In keeping with the literature, the IGHV gene repertoire of the present cohort was remarkably biased, with the IGHV3–21, IGHV4–34, IGHV3–23 and IGHV1–8 genes accounting for 55.1% of cases. Profiling of AID mRNA expression was performed by RQ-PCR for the full-length AID (AID-FL) as well as the most frequent splice variants, namely AID-ΔE4a (lacking the first 30 nucleotides from exon 4), and AID-ΔE4 (loss of the entire exon 4). AID transcript levels were calculated as the percentage of AID copy number divided by the copy number of the reference transcript (c-ABL). AID-FL transcripts were detected in 104/107 (97%) cases whereas the AID-ΔE4a and AID-ΔE4 splice variants were detected in 72/107 (67.3%) and 107/107 cases (100%), respectively. The median values for AID-FL, AID-ΔE4a and AID-ΔE4 transcripts were 4.45%, 0.133% and 0.918%, respectively. AID transcript levels varied between different cases by up to 5-log for AID-FL transcripts and 4-log for splice variants. Not unexpectedly, the median transcript levels in LN samples were higher (up to 1-log) compared to PB samples. A highly significant (p<0.001) association was noted between medium-to-high AID-FL transcript levels (AID-FL/ABL○1%) and IGHV GI 100%. Given the difference in tissue origin of our samples, we also performed a separate analysis for LN samples only and found that cases with 100% IGHV GI expressed high AID-FL transcript levels (AID-FL/ABL○10%) significantly (p=0.04) more frequently than cases carrying mutated IGHV genes. Isotype switch events were investigated in 41 cases: overall, 4 cases (9.7%), all with GI<100%, carried alternative tumor-derived Cγ (n=1) or Cα (n=3) transcripts. In conclusion, the present analysis documents AID expression in the vast majority of MCL, thus corroborating our previous hypothesis for antigen involvement in MCL ontogeny. Ongoing CSR events appear to be a feature of MCL, further supporting an activated status, at least for subset of cases. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A/T mutagenesis in hypermutated immunoglobulin genes strongly depends on PCNAK164 modification

2007 ◽  
Vol 204 (8) ◽  
pp. 1989-1998 ◽  
Author(s):  
Petra Langerak ◽  
Anders O.H. Nygren ◽  
Peter H.L. Krijger ◽  
Paul C.M. van den Berk ◽  
Heinz Jacobs
Keyword(s):  
B Cells ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Nuclear Antigen ◽  
Translesion Dna Synthesis ◽  
Class Switch ◽  
Activation Induced Cytidine Deaminase ◽  
Mismatch Recognition ◽  
Proliferating Cell

B cells use translesion DNA synthesis (TLS) to introduce somatic mutations around genetic lesions caused by activation-induced cytidine deaminase. Monoubiquitination at lysine164 of proliferating cell nuclear antigen (PCNAK164) stimulates TLS. To determine the role of PCNAK164 modifications in somatic hypermutation, PCNAK164R knock-in mice were generated. PCNAK164R/K164R mutants are born at a sub-Mendelian frequency. Although PCNAK164R/K164R B cells proliferate and class switch normally, the mutation spectrum of hypermutated immunoglobulin (Ig) genes alters dramatically. A strong reduction of mutations at template A/T is associated with a compensatory increase at G/C, which is a phenotype similar to polymerase η (Polη) and mismatch repair–deficient B cells. Mismatch recognition, monoubiquitinated PCNA, and Polη likely cooperate in establishing mutations at template A/T during replication of Ig genes.

Chronic lymphocytic leukemia B cells expressing AID display dissociation between class switch recombination and somatic hypermutation

Blood ◽  
2003 ◽  
Vol 101 (10) ◽  
pp. 4029-4032 ◽  
Author(s):  
Pablo Oppezzo ◽  
Françoise Vuillier ◽  
Yuri Vasconcelos ◽  
Gérard Dumas ◽  
Christian Magnac ◽  
...  
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Gene Product ◽  
Mode Of Action ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Class Switch Recombination ◽  
Lymphocytic Leukemia ◽  
Class Switch ◽  
Activation Induced Cytidine Deaminase

Abstract In B cells, somatic hypermutation (SHM) and class switch recombination (CSR) depend on the activation-induced cytidine deaminase (AID) gene product, although the precise mode of action of AID remains unknown. Because some chronic lymphocytic leukemia (CLL) B cells can undergo CSR without SHM, it constitutes a useful model to dissect AID function. In this work, we have studied AID expression, the presence of mutations in the preswitch μ DNA region, CSR, and the SHM in 65 CLL patients. Our results demonstrate that unmutated CLL B cells can constitutively express AID and that AID expression is associated with the presence of mutations in the preswitch region and in clonally related isotype-switched transcripts. They also demonstrate that in CLL without constitutive AID expression, AID induction on stimulation results in preswitch mutations and the CSR process. Our results show a dissociation between SHM and CSR in CLL and suggest that, in this disease, AID would require additional help for carrying out the SHM process.

scholarly journals Strand-biased defect in C/G transversions in hypermutating immunoglobulin genes in Rev1-deficient mice

2006 ◽  
Vol 203 (2) ◽  
pp. 319-323 ◽  
Author(s):  
Jacob G. Jansen ◽  
Petra Langerak ◽  
Anastasia Tsaalbi-Shtylik ◽  
Paul van den Berk ◽  
Heinz Jacobs ◽  
...  
Keyword(s):  
B Cells ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Translesion Synthesis ◽  
Uracil Dna Glycosylase ◽  
Abasic Sites ◽  
Activation Induced Cytidine Deaminase ◽  
Deficient Mice

Somatic hypermutation of Ig genes enables B cells of the germinal center to generate high-affinity immunoglobulin variants. Key intermediates in somatic hypermutation are deoxyuridine lesions, introduced by activation-induced cytidine deaminase. These lesions can be processed further to abasic sites by uracil DNA glycosylase. Mutagenic replication of deoxyuridine, or of its abasic derivative, by translesion synthesis polymerases is hypothesized to underlie somatic hypermutation. Rev1 is a translesion synthesis polymerase that in vitro incorporates uniquely deoxycytidine opposite deoxyuridine and abasic residues. To investigate a role of Rev1 in mammalian somatic hypermutation we have generated mice deficient for Rev1. Although Rev1−/− mice display transient growth retardation, proliferation of Rev1−/− LPS-stimulated B cells is indistinguishable from wild-type cells. In mutated Ig genes from Rev1−/− mice, C to G transversions were virtually absent in the nontranscribed (coding) strand and reduced in the transcribed strand. This defect is associated with an increase of A to T, C to A, and T to C substitutions. These results indicate that Rev1 incorporates deoxycytidine residues, most likely opposite abasic nucleotides, during somatic hypermutation. In addition, loss of Rev1 causes compensatory increase in mutagenesis by other translesion synthesis polymerases.

Different Isoforms of BSAP Protein Regulate the Expression of Activation-Induced Cytidine Deaminase (AID) in Normal and CLL B-Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1901-1901
Author(s):  
Pablo J. Oppezzo ◽  
Gerard M. Dumas ◽  
Ana Ines Lalanne ◽  
Otto F. Pritsch ◽  
Francoise M. Vuillier ◽  
...  
Keyword(s):  
B Cells ◽  
Molecular Mechanisms ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Gene Promoter ◽  
Cd40 Ligand ◽  
Regulation Mechanism ◽  
Class Switch ◽  
Healthy Donors ◽  
Typical Event

Abstract Background: In B-cells somatic hypermutation (SHM) and class switch recombination (CSR) depend of AID expression, a typical event in germinal centers upon CD40 ligand (CD40L) stimulation. We recently showed, that in contrast to normal B-cells, AID is constitutively expressed in a majority of unmutated CLL patients (Oppezzo et al, Blood, 2003). Pax-5 gene, encodes for the B-specific activator protein (BSAP) an essential protein in B-cell development. BSAP has been shown to up-regulate AID gene expression, through binding to its promoter region, whereas inhibitor of differentiation Id-2 down-regulates it. To study the molecular mechanisms underlying AID regulation, we analyzed expression of BSAP and Id-2 transcripts in normal and CLL B-cells and correlated these results to expression of AID and CSR process. Results: B-cells from 6 healthy donors and 40 CLL patients were analyzed for Pax-5, Id-2, AID and CSR. Results show that CLL and normal B-cells not expressing AID exhibit diminished expression of BSAP and express a spliced variant of the Pax-5 gene (Pax-5 ΔEx8) displaying a deletion in the C-terminal-active domain. Upon CD40-L and IL-4 stimulation expression of AID transcripts and disappearance of the Pax-5 ΔEx8 transcripts was observed. Translation of complete Pax-5 and Pax-5/ΔEx8 isoforms and their binding to AID gene promoter have been demonstrated by Western Blot and EMSA assays, respectively. In contrast, CLL B-cells with constitutive AID expression and active CSR, constantly show increased levels of BSAP and absence of Pax-5ΔEx8 isoform. High expression of AID and BSAP is also correlated with a decrease of Id-2 transcripts. Conclusion: These results suggest that the presence of BSAP isoform deleted in exon 8 may interfere with the binding of the complete BSAP protein to AID promoter and down-regulate the expression of Pax-5a. Thus, we show for the first time a subtle regulation mechanism controlling the expression of AID protein through the differential splicing of a transcription factor as BSAP.

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