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Prepublished online as a Blood First Edition Paper on December 19, 2002; DOI 10.1182/blood-2002-11-3387.
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Blood, 15 April 2003, Vol. 101, No. 8, pp. 2914-2923
PLENARY PAPER
Mutations of the BCL6 proto-oncogene disrupt its
negative autoregulation in diffuse large B-cell lymphoma
Laura Pasqualucci,
Anna Migliazza,
Katia Basso,
Jane Houldsworth,
R. S. K. Chaganti, and
Riccardo Dalla-Favera
From the Institute for Cancer Genetics and the
Departments of Pathology and of Genetics and Development, Columbia
University, New York; and the Laboratory of Cancer Genetics and the
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New
York, NY.
The BCL6 proto-oncogene encodes a
transcriptional repressor whose expression is deregulated by
chromosomal translocations in approximately 40% of diffuse large
B-cell lymphomas (DLBCLs). The BCL6 regulatory sequences
are also targeted by somatic hypermutation in germinal center (GC) B
cells and in a fraction of all GC-derived lymphomas. However, the
functional consequences of these mutations are unknown. Here we report
that a subset of mutations specifically associated with DLBCL causes
deregulated BCL6 transcription. These mutations affect 2 adjacent BCL6
binding sites located within the first noncoding exon of the gene, and
they prevent BCL6 from binding its own promoter, thereby disrupting its
negative autoregulatory circuit. These alterations were found in
approximately 16% of DLBCLs devoid of chromosomal translocations
involving the BCL6 locus, but they were not found in normal GC B cells.
This study establishes a novel mechanism for BCL6 deregulation and
reveals a broader involvement of this gene in DLBCL pathogenesis.
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