Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma

Blood - Tập 101 Số 8 - Trang 2914-2923 - 2003
Laura Pasqualucci1, Anna Migliazza1,2, Katia Basso1,2, Jane Houldsworth1,2, R. S. K. Chaganti1,2, Riccardo Dalla‐Favera1,2
1From 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.
2Institute for Cancer Genetics and the Departments of Pathology and of Genetics and Development, Columbia University, New York

Tóm tắt

Abstract 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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Blood

Tập 101 Số 8

2914-2923

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