Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Aged, 80 and over
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B-Lymphocytes / immunology*
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B-Lymphocytes / metabolism
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B-Lymphocytes / pathology
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Base Sequence
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CD40 Ligand
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Cytidine Deaminase
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Cytosine Deaminase / immunology*
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Cytosine Deaminase / metabolism
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Female
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Gene Expression Regulation, Enzymologic / immunology*
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Gene Expression Regulation, Leukemic / immunology*
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Humans
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Inhibitor of Differentiation Protein 2 / immunology
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Inhibitor of Differentiation Protein 2 / metabolism
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Leukemia, Lymphocytic, Chronic, B-Cell / immunology*
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Male
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Middle Aged
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PAX5 Transcription Factor / immunology*
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PAX5 Transcription Factor / metabolism
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Positive Regulatory Domain I-Binding Factor 1
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Protein Isoforms / immunology
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Protein Isoforms / metabolism
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Repressor Proteins / immunology
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Repressor Proteins / metabolism
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Sequence Deletion / immunology
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Somatic Hypermutation, Immunoglobulin / immunology
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Transcription Factors / immunology
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Transcription Factors / metabolism
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Transcription, Genetic / immunology
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Tumor Cells, Cultured
Substances
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ID2 protein, human
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Inhibitor of Differentiation Protein 2
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PAX5 Transcription Factor
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PAX5 protein, human
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Protein Isoforms
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Repressor Proteins
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Transcription Factors
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PRDM1 protein, human
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CD40 Ligand
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Positive Regulatory Domain I-Binding Factor 1
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AICDA (activation-induced cytidine deaminase)
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Cytosine Deaminase
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Cytidine Deaminase