Different isoforms of BSAP regulate expression of AID in normal and chronic lymphocytic leukemia B cells.
Activation-induced cytidine deaminase (AID) is key to initiating somatic hypermutation (SHM) and class switch recombination (CSR), but its mode of action and regulation remains unclear. Since Pax-5 and Id-2 transcription factors play an opposing role in AID regulation, we have studied the expression of Pax-5, Id-2, and prdm-1 genes in 54 chronic lymphocytic leukemia (CLL) B cells. In 21 cases, presence of AID is constantly associated with high expression of the complete form of the Pax-5 gene (Pax-5a) and lower expression of the Id-2 and prdm-1 transcripts. In 33 cases, the absence of AID expression and CSR is associated with a reduction of Pax-5a and the appearance of a spliced form with a deletion in exon 8 (Pax-5/Delta-Ex8). Stimulation with CD40L+interleukin 4 (IL-4) induces CSR, the presence of AID transcripts, up-regulation of Pax-5a and down-regulation of Pax-5/Delta-Ex8, and Id-2 and prdm-1 transcripts. Pax-5a and Pax-5/Delta-Ex8 are translated into 2 isoforms of the B-cell-specific activator protein (BSAP) and both are able to bind the AID-promoter region. Overall, these results suggest that Pax-5/Delta-Ex8 could play an important role in the control of its own transcription and indirectly in AID expression and CSR.
Oppezzo
Pablo
P
Unité d'Immuno-hématologie et d'Immunopathologie, Institut Pasteur, 28 Rue Docteur Roux, 75015 Paris, France. poppezzo@pasteur.fr
Dumas
Gérard
G
Lalanne
Ana Inés
AI
Payelle-Brogard
Béatrice
B
Magnac
Christian
C
Pritsch
Otto
O
Dighiero
Guillaume
G
Vuillier
Françoise
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D023201:CD40 Ligand; D003564:Cytidine Deaminase; D043525:Cytosine Deaminase / Q000276:immunology* / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000276:immunology*; D015973:Gene Expression Regulation, Leukemic / Q000276:immunology*; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000276:immunology / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D051757:PAX5 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D020033:Protein Isoforms / Q000276:immunology / Q000378:metabolism; D012097:Repressor Proteins / Q000276:immunology / Q000378:metabolism; D017384:Sequence Deletion / Q000276:immunology; D027041:Somatic Hypermutation, Immunoglobulin / Q000276:immunology; D014157:Transcription Factors / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology; D014407:Tumor Cells, Cultured; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D020033:Protein Isoforms; D012097:Repressor Proteins; D014157:Transcription Factors; C087042:PRDM1 protein, human; D023201:CD40 Ligand; D000074462:Positive Regulatory Domain I-Binding Factor 1; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D043525:Cytosine Deaminase; D003564:Cytidine Deaminase