title: Deregulated PAX-5 transcription from a translocated IgH promoter in marginal zone lymphoma.
abstract: The PAX-5 gene codes for the transcription factor BSAP, which is expressed throughout B-cell development. Although loss-of-function mutation in the mouse showed an essential role for Pax-5 in early B lymphopoiesis, gain-of-function mutations have implicated the human PAX-5 gene in the control of late B-cell differentiation. PAX-5 (on 9p13) has been involved together with the immunoglobulin heavy-chain (IgH) gene (on 14q32) in the recurring t(9;14)(p13;q32) translocation that is characteristic of small lymphocytic lymphoma with plasmacytoid differentiation. Here we have characterized a complex t(2;9;14)(p12;p13;q32) translocation present in a closely related non-Hodgkin's lymphoma referred to as splenic marginal zone lymphoma (MZL). In this MZL-1 translocation, the two promoters of PAX-5 were replaced on the derivative chromosome 14 by an immunoglobulin switch Smicro promoter that was linked to the structural PAX-5 gene upstream of its translation initiation codon in exon 1B. Expression analyses confirmed that PAX-5 transcription was upregulated due to efficient initiation at the Smicro promoter in the malignant B lymphocytes of patient MZL-1. For comparison we have analyzed PAX-5 expression in another B-cell lymphoma, KIS-1, indicating that transcription from the distal PAX-5 promoter was increased in this tumor in agreement with the previously characterized translocation of the immunoglobulin Emicro; enhancer adjacent to PAX-5 exon 1A. In both lymphomas, the J-chain gene, which is thought to be under negative control by BSAP, was not expressed, whereas transcription of the putative target gene p53 was unaffected by PAX-5 overexpression. Together these data indicate that the t(9;14)(p13;q32) translocation contributes to lymphoma formation as a regulatory mutation that leads to increased PAX-5 expression in late B-cell differentiation due to promoter replacement or enhancer insertion.
authors.affiliation: Research Institute of Molecular Pathology, Vienna, Austria; the University of Vienna Medical School, Vienna, Austria; and St. Anna Children's Hospital, Vienna, Austria.
authors.forename: A M
authors.initials: AM
authors.lastname: Morrison
authors.forename: U
authors.initials: U
authors.lastname: Jäger
authors.forename: A
authors.initials: A
authors.lastname: Chott
authors.forename: M
authors.initials: M
authors.lastname: Schebesta
authors.forename: O A
authors.initials: OA
authors.lastname: Haas
authors.forename: M
authors.initials: M
authors.lastname: Busslinger
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D001483:Base Sequence; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics* / Q000648:ultrastructure; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics* / Q000648:ultrastructure; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005801:Genes, Homeobox; D005803:Genes, Immunoglobulin; D005812:Genes, Switch; D016158:Genes, p53; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007621:Karyotyping; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D051757:PAX5 Transcription Factor; D011401:Promoter Regions, Genetic; D014157:Transcription Factors; D014178:Translocation, Genetic
chemical_list: D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; D009687:Nuclear Proteins; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D014157:Transcription Factors