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- Afshari, Maryam K., et al.
(author)
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Activation of PLAG1 and HMGA2 by gene fusions involving the transcriptional regulator gene NFIB
- 2020
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In: Genes Chromosomes & Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 59:11, s. 652-660
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Journal article (peer-reviewed)abstract
- The pleomorphic adenoma (PA), which is the most common salivary gland neoplasm, is a benign tumor characterized by recurrent chromosome rearrangements involving 8q12 and 12q14-15. We have previously shown that thePLAG1andHMGA2oncogenes are the targets of these rearrangements. Here, we have identified previously unrecognized subsets of PAs with ins(9;8)/t(8;9) (n = 5) and ins(9;12)/t(9;12) (n = 8) and breakpoints located in the vicinity of thePLAG1andHMGA2loci. RNA-sequencing and reverse transcriptase (RT)-PCR analyses of a case with an ins(9;8) revealed a novelNFIB-PLAG1fusion in whichNFIBexon 4 is linked toPLAG1exon 3. In contrast to the developmentally regulatedPLAG1gene,NFIBwas highly expressed in normal salivary gland, indicating thatPLAG1in this case, as in other variant fusions, is activated by promoter swapping. RT-PCR analysis of three PAs with t(9;12) revealed two tumors with chimeric transcripts consisting ofHMGA2exon 4 linked toNFIBexons 9 or 3 and one case with a fusion linkingHMGA2exon 3 toNFIBexon 9. TheNFIBfusion events resulted in potent activation ofPLAG1andHMGA2. Analysis of the chromatin landscape surroundingNFIBrevealed several super-enhancers in the 5 '- and 3 '-parts of theNFIBlocus and its flanking sequences. These findings indicate thatPLAG1andHMGA2, similar toMYBin adenoid cystic carcinoma, may be activated by enhancer-hijacking events, in which super-enhancers inNFIBare translocated upstream ofPLAG1or downstream ofHMGA2. Our results further emphasize the role ofNFIBas a fusion partner to multiple oncogenes in histopathologically different types of salivary gland tumors.
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| 2. |
- Andersson, Mattias K, 1979, et al.
(author)
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ATR is a MYB regulated gene and potential therapeutic target in adenoid cystic carcinoma
- 2020
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In: Oncogenesis. - : Springer Science and Business Media LLC. - 2157-9024. ; 9
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Journal article (peer-reviewed)abstract
- Adenoid cystic carcinoma (ACC) is a rare cancer that preferentially occurs in the head and neck, breast, as well as in other sites. It is an aggressive cancer with high rates of recurrence and distant metastasis. Patients with advanced disease are generally incurable due to the lack of effective systemic therapies. Activation of the master transcriptional regulator MYB is the genomic hallmark of ACC. MYB activation occurs through chromosomal translocation, copy number gain or enhancer hijacking, and is the key driving event in the pathogenesis of ACC. However, the functional consequences of alternative mechanisms of MYB activation are still uncertain. Here, we show that overexpression of MYB or MYB-NFIB fusions leads to transformation of human glandular epithelial cells in vitro and results in analogous cellular and molecular consequences. MYB and MYB-NFIB expression led to increased cell proliferation and upregulation of genes involved in cell cycle control, DNA replication, and DNA repair. Notably, we identified the DNA-damage sensor kinase ATR, as a MYB downstream therapeutic target that is overexpressed in primary ACCs and ACC patient-derived xenografts (PDXs). Treatment with the clinical ATR kinase inhibitor VX-970 induced apoptosis in MYB-positive ACC cells and growth inhibition in ACC PDXs. To our knowledge, ATR is the first example of an actionable target downstream of MYB that could be further exploited for therapeutic opportunities in ACC patients. Our findings may also have implications for other types of neoplasms with activation of the MYB oncogene.
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