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

Abstract

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-offunction activity resulting from the MYB-NFIB fusion is a candidate therapeutic target.chromosome translocation ͉ fusion oncogene ͉ miRNA ͉ adenoid cystic carcinoma F usion genes are potent oncogenes resulting from chromosome rearrangements, in particular translocations. Most fusion genes identified thus far have been in hematological disorders and mesenchymal neoplasms, and only a few have been found in carcinomas (1). This paucity probably results from an inability to discover these rearrangements rather than from a true lack of such genes in carcinomas. The recent discovery that the majority of prostate cancers harbor ETS gene fusions (2) is in line with this reasoning. Finding as yet unidentified fusion oncogenes in other carcinomas could provide important insights into the molecular pathogenesis of these cancers and also might facilitate the development of new targeted therapies.We previously have identified a recurrent and tumor-specific t(6;9)(q22-23;p23-24) translocation in adenoid cystic carcinoma (ACC) of the head and neck (3). The translocation has been found as the sole cytogenetic anomaly in several cases, indicating that it is a primary rearrangement in this carcinoma.ACC has been known as a histologically distinctive neoplasm for nearly 150 years. It is among the most common carcinomas of the salivary glands (4) but also may arise in other exocrine glands, such as in the breast, and in the cervix, vulva, and tracheobronchial tree (5). ACC usually is an aggressive, although slowly growing, cancer with a long-term poor prognosis. Most patients (80-90%) with ACC ...

Mammary Analogue Secretory Carcinoma of Salivary Gland Origin: An Update and Expanded Morphologic and Immunohistochemical Spectrum of Recently Described Entity

“…The identification of ETV6-NTRK3 fusion in MASC adds yet another gene fusion to the growing list of chimeric genes of diagnostic importance for salivary gland carcinomas. Previous studies have shown that mucoepidermoid carcinomas are characterized by CRTC1/ CRTC3-MAML2 or EWSR1-POU5F1 fusions [24,25] and adenoid cystic carcinomas by MYB-NFIB fusions [26]. In addition, Antonescu et al [27] recently identified a consistent EWSR1-ATF1 fusion in hyalinizing clear cell carcinoma of minor salivary glands.…”

A functional SUMO-interacting motif in the transactivation domain of c-Myb regulates its myeloid transforming ability

“…This is surprising because there is generally strong correlation between transactivation and transformation by c-Myb (Hu et al, 1991), and the importance of functional co-activation by CBP/p300 (Pattabiraman et al, 2009) and menin/MLL (Jin et al, 2010) has been shown. In cancers linked to aberrations involving the MYB locus, increased c-Myb dosage, and hence activity, seems to be a common theme (Clappier et al, 2007;Lahortiga et al, 2007;Persson et al, 2009). Nevertheless, the 2KR and ANAA mutants described here seem to partially dissociate transactivation from transformation.…”

“…The MYB locus is rearranged in several human neoplasias, with increased expression as a frequent outcome. This can be caused by translocation, leading to deregulation of the MYB gene, as in childhood T-cell acute lymphoblastic leukemia (Clappier et al, 2007), or stabilization of MYB mRNA, as in adenoid cystic carcinomas of the breast, head and neck (Persson et al, 2009). Local duplication of MYB has also been reported with another subgroup of T-cell acute lymphoblastic leukemia (Clappier et al, 2007;Lahortiga et al, 2007) and in a subgroup of acute myelomonocytic leukemia (Murati et al, 2009).…”

Adenoid cystic carcinoma: A review of recent advances, molecular targets, and clinical trials

“…This could be explained by autocrine activation of the receptor driven by concomitant expression of one its ligands, FGF2. This growth factor is upregulated in ACC cells with MYB overexpression and therefore is a candidate downstream effector of this oncoprotein 33, 77. The relevance of FGF signaling to ACC tumorigenesis is further supported by the description of mutations in the FGF14 , FGFR4 , or FGFR2 genes in 4 different tumors 24, 25.…”