Identification of NFIB as recurrent translocation partner gene of HMGIC in pleomorphic adenomas

Jm, Geurts; Ef, Schoenmakers; Röijer, Eva; Ak, Aström; Stenman, Göran; Wj, Van de Ven

doi:10.1038/sj.onc.1201609

Cited by 137 publications

(147 citation statements)

References 24 publications

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“…Interestingly, recent studies have shown that the expression of HMGA2, another oncogene frequently activated by chromosomal translocations, also is deregulated by the loss of negatively regulating Let-7 miRNA target sites in the 3Ј UTR of HMGA2 as a consequence of gene fusions (24,25). In a small subset of these cases, the activation is the result of fusions of the last 5 amino acids of the NFIB protein to the DNA binding domains of HMGA2 (6,8), the same part of NFIB that is fused to MYB in ACC. Our findings thus may represent a second example of miRNAdirected repression of an oncogene activated by chromosomal translocations.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…Using FISH and a panel of yeast artificial chromosome (YAC) clones derived from 9p23-24 (6), we found that YAC-912E9 spanned the 9p23-24 breakpoint in an ACC with a t(6;9). This YAC contains NFIB, a member of the human nuclear factor I (NFI) gene family of transcription factors, as the only named gene (6). NFI proteins contain DNA binding and dimerization domains in their N-termini and proline-rich, transactivation domains in their C-termini (7).…”

Section: Resultsmentioning

confidence: 99%

“…NFI proteins contain DNA binding and dimerization domains in their N-termini and proline-rich, transactivation domains in their C-termini (7). Interestingly, we previously have identified NFIB as a recurrent fusion partner to HMGA2 in benign pleomorphic salivary gland adenomas with t(9;12) translocations (6,8).Initial FISH mapping of the 6q22-24 translocation breakpoint revealed that it is located proximal to the PLAGL1 locus in 6q24-25 (9). Further analysis using a panel of bacterial artificial chromosome (BAC) clones derived from 6q22-24 (available on request) revealed that the breakpoint is located within a 1…”

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confidence: 99%

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

Persson

Andrén

Mark

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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705

639

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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 ...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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

Persson

Andrén

Mark

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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705

639

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“…The high mobility group protein gene, HMGIC, is implicated in a variety of salivary gland adenomas and other benign tumors. Thus, it is of interest that FHIT has also been involved in somatic rearrangement t(3;12) in a benign adenomas of the parotid gland (Geurts et al, 1997). Again this translocation produced a fusion HMGIC/FHIT transcript together with normal FHIT transcript.…”

Section: Chromosome Region 3p142 (Fhit Gene Region)mentioning

confidence: 99%

Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers

Zabarovsky¹,

2002

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Loss of heterozygosity (LOH) involving several chromosome 3p regions accompanied by chromosome 3p deletions are detected in almost 100% of small (SCLCs) and more than 90% of non-small (NSCLCs) cell lung cancers. In addition, these changes appear early in the pathogenesis of lung cancer and are found as clonal lesions in the smoking damaged respiratory epithelium including histologically normal epithelium as well as in epithelium showing histologic changes of preneoplasia. These 3p genetic alterations lead to the conclusion that the short arm of human chromosome 3 contains several tumor suppressor gene(s) (TSG(s)). Although the first data suggesting that 3p alterations were involved in lung carcinogenesis were published more than 10 years ago, only recently has significant progress been achieved in identifying the candidate TSGs and beginning to demonstrate their functional role in tumor pathogenesis. Some of the striking results of these findings has been the discovery of multiple 3p TSGs and the importance of tumor acquired promoter DNA methylation as an epigenetic mechanism for inactivating the expression of these genes in lung cancer. This progress, combined with the well known role of smoking as an environmental causative risk factor in lung cancer pathogenesis, is leading to the development of new diagnostic and therapeutic strategies which can be translated into the clinic to combat and prevent the lung cancer epidemic. It is clear now that genetic and epigenetic abnormalities of several genes residing in chromosome region 3p are important for the development of lung cancers but it is still obscure how many of them exist and which of the numerous candidate TSGs are the key players in lung cancer pathogenesis. We review herein our current knowledge and describe the most credible candidate genes.

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Fluorescence in situ hybridization mapping of breakpoints in pleomorphic adenomas with 8q12-13 abnormalities identifies a subgroup of tumors withoutPLAG1 involvement

Röijer

Kas

Behrendt

et al. 1999

Genes Chromosom. Cancer

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Identification of NFIB as recurrent translocation partner gene of HMGIC in pleomorphic adenomas

Cited by 137 publications

References 24 publications

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

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

Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers

Fluorescence in situ hybridization mapping of breakpoints in pleomorphic adenomas with 8q12-13 abnormalities identifies a subgroup of tumors withoutPLAG1 involvement

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