Negative autoregulation of BCL-6 is bypassed by genetic alterations in diffuse large B cell lymphomas.
Thirty to forty percent of diffuse large B cell lymphomas (DLBCL) carry BCL-6 translocations that disrupt its 5' regulatory region. This same region is also subject to somatic hypermutations, although only a small fraction of these mutations have a detectable effect on transcription. Here, we show that transcription of the BCL-6 gene is negatively self-regulated in multiple cell types. This mechanism operates by means of the interaction of two BCL-6-binding sites within exon 1 of the gene and the BCL-6 protein itself, which is a potent transcription repressor. Because the DLBCL-associated "activating mutations" specifically target these exon 1 binding sites, and because the entire exon 1 is usually removed in the BCL-6-translocated tumors, this autoregulation is bypassed in 30-40% of all DLBCL cases. Our results not only demonstrate an important mechanism governing the expression of BCL-6, but also explain how BCL-6 is deregulated in a large number of DLBCL patients, providing a better understanding of BCL-6-related lymphomagenesis.
Wang
Xing
X
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Li
Zhiping
Z
Naganuma
Akira
A
Ye
B Hilda
BH
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D002843:Chromatin / Q000235:genetics / Q000276:immunology; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006706:Homeostasis; D006801:Humans; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D014162:Transfection; D014178:Translocation, Genetic
D002843:Chromatin; D017931:DNA Primers; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D012333:RNA, Messenger; D014157:Transcription Factors