Negative autoregulation of BCL-6 is bypassed by genetic alterations in diffuse large B cell lymphomas

Xing Wang, Zhiping Li, Akira Naganuma, B. Hilda Ye

Research output: Contribution to journalArticle

89 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)15018-15023
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number23
DOIs
StatePublished - Nov 12 2002

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Lymphoma, Large B-Cell, Diffuse
Homeostasis
Exons
Binding Sites
Mutation
Nucleic Acid Regulatory Sequences
Genes
Neoplasms
Proteins

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Negative autoregulation of BCL-6 is bypassed by genetic alterations in diffuse large B cell lymphomas. / Wang, Xing; Li, Zhiping; Naganuma, Akira; Ye, B. Hilda.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 99, No. 23, 12.11.2002, p. 15018-15023.

Research output: Contribution to journalArticle

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AB - 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.

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