Journal Article

Recurrent fusion of MYB and NFIB transcription factor genes in carcinomas of the breast and head and neck

Persson, Marta, Horlings, Hugo M, Stenman, Göran, Mark, Joachim, Andrén, Ywonne, Persson, Fredrik

2009

Overview

The transcription factor gene MYB was identified recently as an oncogene that is rearranged/duplicated in some human leukemias. Here we describe a new mechanism of activation of MYB in human cancer involving gene fusion. We show that the t(6;9)(q22-23;p23-24) translocation in adenoid cystic carcinomas (ACC) of the breast and head and neck consistently results in fusions encoding chimeric transcripts predominantly consisting of MYB exon 14 linked to the last coding exon(s) of NFIB. The minimal common part of MYB deleted as the result of fusion was exon 15 including the 3'-UTR, which contains several highly conserved target sites for miR-15a/16 and miR-150 microRNAs. These microRNAs recently were shown to regulate MYB expression negatively. We suggest that deletion of these target sites may disrupt repression of MYB leading to overexpression of MYB-NFIB transcripts and protein and to activation of critical MYB targets, including genes associated with apoptosis, cell cycle control, cell growth/angiogenesis, and cell adhesion. Forced overexpression of miR-15a/16 and miR-150 in primary fusion-positive ACC cells did not significantly alter the expression of MYB as compared with leukemic cells with MYB activation/duplication. Our data indicate that the MYB-NFIB fusion is a hallmark of ACC and that deregulation of the expression of MYB and its target genes is a key oncogenic event in the pathogenesis of ACC. Our findings also suggest that the gain-of-function activity resulting from the MYB-NFIB fusion is a candidate therapeutic target.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: 3' untranslated regions / Adenoid cystic carcinoma / Adenoid Cystic/genetics/pathology / Adult / Adult T-Cell/genetics / Aged / angiogenesis / apoptosis / Base Sequence / Biological Sciences / Breast cancer / Breast Neoplasms - genetics / Breast Neoplasms - pathology / Breast Neoplasms/genetics/pathology / Carcinoma / Carcinoma, Adenoid Cystic - genetics / Carcinoma, Adenoid Cystic - pathology / cell adhesion / Cell and Molecular Biology / cell cycle / cell growth / Cell lines / Cell- och molekylärbiologi / Cells / Chromosomes / Chromosomes, Human, Pair 6 - genetics / Chromosomes, Human, Pair 8 - genetics / Deregulation / Exons / Female / Fusion/genetics/metabolism / gain-of-function mutation / Gene expression / Gene Expression Regulation / Gene Expression Regulation, Neoplastic / gene fusion / gene overexpression / Genes / Genetic / Head / Head & neck cancer / Head and Neck Neoplasms - genetics / Head and Neck Neoplasms - pathology / Head and Neck Neoplasms/genetics/pathology / Human / Humans / Leukemia / Leukemia-Lymphoma / Leukemia-Lymphoma, Adult T-Cell - genetics / Male / Messenger/genetics/metabolism / MicroRNA / MicroRNAs - genetics / Middle Aged / Molecular Sequence Data / neck / Neoplastic / Oncogene Proteins / Oncogene Proteins, Fusion - genetics / Oncogene Proteins, Fusion - metabolism / Oncogenes / Pair 6/genetics / Pair 8/genetics / pathogenesis / Proteins / RNA / RNA, Messenger - genetics / RNA, Messenger - metabolism / Salivary glands / transcription (genetics) / transcription factors / Transfection / Translocation / Translocation, Genetic / Tumors