The nfib gene also encodes a transcription factor, nuclear factor ib nfib, a key regulator in hematopoietic and epithelial cells, raising the possibility that the myb nfib fusion genes encode novel regulators with the dna binding domain of c myb fused to the specificity and activation domains of nfib. Transgenic models with inducible overexpression of the mybnfib fusion in the salivary gland compartment are in development. Intriguingly, the fusion is regulated through aktdependent signaling induced by igf1r overexpression and is downregulated upon igf1rinhibition % expression of control sd 27. Mybnfib gene fusion in adenoid cystic carcinoma of the. Order 5 or more of the nfib fish probe and save 10%. At least 100 nuclei were evaluated per tissue section using a fluorescence microscope olympus bx51. Access expert resources to help you grow your business.
Breakpoints in myb and nfib a and mybl1 and nfib b found to be fused to each other are shown in the same color. To determine whether the myb nfib fusion is a recurrent event in acc, we screened tumor rnas from 10 additional primary and metastatic accs, including 6 head and neckderived and 4 breastderived tumors table 1. Nfib gene fusion has not been observed in any nonacc carcinomas of the head and neck to date 11. All inventions from nci office of technology transfer, nih. Although fluorescent in situ hybridization fish is an efficient tool, particularly in the detection of mybmybl1nfib fusion genes in acc or plag1hmga2 rearrangement in pa, a hotspot mutation analysis by direct dna sequencingas reported in our studyis a simple, stable, and costeffective method in comparison with fish. Oct 14, 2009 recurrent fusion of the myb and nfib transcription factor genes in carcinomas of the breast and head and neck. Mybnfib gene fusions identified in archival adenoid.
Studies of the human c myb gene and its product in human acute leukemias. Here, we show that overexpression of myb or mybnfib fusions leads to. Myb labeling by immunohistochemistry is more sensitive and s. Published articles adenoid cystic carcinoma research foundation. Among its related pathways are activated pkn1 stimulates transcription of ar androgen receptor regulated genes klk2 and klk3 and rna polymerase.
Atr is a myb regulated gene and potential therapeutic target. To uncover the genetic alterations in acc lacking the. The mybnfib gene fusion is the main genomic hallmark and a potential therapeutic target. Reverse transcription polymerase chain reaction rtpcr analysis was conducted on rnas isolated from the ffpe blocks of both tumors using pcrprimers located in myb exon 14 and nfib exons 8a, 8c, and 9 as previously described 19. Analysis of myb expression and mybnfib gene fusions in adenoid. Comprehensive analysis of the myb nfib gene fusion in salivary adenoid cystic carcinoma.
Myb a regulatory factor in hematopoiesis sciencedirect. In summary, our studies show that myb activation through gene fusion. They will help determine whether the fusion is sufficient for tumorigenesis myb overexpression in leukemia models has not been sufficient. Empire genomics nfib fish probe is used to detect translocations of the nfib gene and can be labeled in one of five colors, using standard nick translation protocols. Using locus specific probes for the 2 genes of interest, nuclei with the gene fusion showed 1 yellow signal, indicating fusion of red myb locus and green nfib locus signals, and 2 separate red and green signals, which correspond to the other 2 not fused alleles. The mybnfib fusion transcripts were amplified by direct or nested pcr. Wholegenome sequencing of salivary gland adenoid cystic. Recurrent rearrangements of the mybsantlike dnabinding. Mybnfib fusion transcript was detected in 25 of 29 86% frozen adenoid. Breakpoints in myb nfib and mybl1 nfib fusion transcripts. Sep 22, 2016 of these 6 cases with a disturbed nfib, only 2 cases 33. This probe is fish confirmed on normal peripheral blood metaphase spreads and interphase nuclei. Rna isolated from twentyfive archival acc specimens was profiled and analyzed.
Cutaneous acc has been found to harbor myb gene activations, either through myb chromosomal abnormalities or by generation of the myb nfib fusion. The nfib gene is a protein coding gene that also serves as a transcription factor. The myb and nfib exons were numbered as described elsewhere 1. Pdf the impact of the mybnfib fusion protooncogene in vivo. Recurrent fusion of myb and nfib transcription factor genes. Myb is a transcription factor which was identified in birds as a viral oncogene v myb. The nfib gene also encodes a transcription factor, nuclear factor ib nfi b, a key regulator in hematopoietic and epithelial cells, raising the possibility that the mybnfib fusion genes encode novel regulators with the dna binding domain of cmyb fused to the specificity and activation domains of nfi b. Diseases associated with nfib include macrocephaly, acquired, with impaired intellectual development and alacrima, achalasia, and mental retardation syndrome. Incidence, variability, and clinicopathologic significance. At least 100 nuclei were evaluated per tissue section. Rtqpcr and sequencing were performed to confirm nanostring results. Recurrent fusion of myb and nfib transcription factor. Mybnfib gene fusions identified in archival adenoid cystic. The predicted myb nfib fusion protein retains the dnabinding and transactivation domains of wild type myb, and is therefore expected to activate myb target genes.
Novel chromosomal rearrangements and break points at the t. Rtpcr analysis revealed myb nfib fusion transcripts in all accs but not in 25 different nonacc tumor samples fig. Different exons in both the myb and nfib genes were involved in the fusions, resulting in. Translocation breakpoints are shown by vertical arrows, and mirna binding sites for mir15a16 and mir150 in the 3. Office of technology transfer, office of intramural research, national institutes of health. Mitani y, li j, rao ph, zhao yj, bell d, lippman sm, weber rs, caulin c, elnaggar ak. This gene is essential in embryonic development and it works together with its gene complex to initiate tissue differentiation in the fetus. Small businesses report q4 is the most profitable time of year. The transcription factor gene myb was identified recently as an oncogene that is rearrangedduplicated in some human leukemias.
However, myb expression was increased in the majority of tumours 69% and global gene expression analysis revealed that well. Targeting the oncogenic transcriptional regulator myb in. Analysis of clinicopathological characteristics, myb. Over the past years, recurrent gene fusions have been identified in several different salivary gland neoplasms 68, including plag1 fusions most often ctnnb1plag1 and hmga2 rearrangements in pleomorphic adenoma, crtc1maml2 fusion in mucoepidermoid carcinoma, mybnfib or mybl1nfib 9, 10 fusion in adenoid cystic carcinoma, etv6ntrk3.
Each probe is sold in 20 test kits 20 slides 22x22 mm area and includes hybridization buffer. The ingenuity variant analysis iva software qiagen was. Jan 30, 2020 in a subset of accs, myb is replaced by the closely related mybl1 gene linked to nfib, or other fusion partners, resulting in gene fusions likely to have the same oncogenic properties as the myb. To uncover the genetic alterations in acc lacking the canonical translocation and fusion. Role of myb and mybnfib fusions in salivary adenoid cystic. Recurrent fusions in myb and mybl1 define a common. The nfib fish probe is designed to hybridize to the nfib gene and is primarily used for detecting amplifications and deletions associated with the gene. Recurrent fusion of the v myb avian myelobastosis viral oncogene homolog myb and nuclear factor ib nfib generates the myb nfib transcription factor, which has been detected in a high.
Phosphoreceptor tyrosine kinase rtk arrays were used to study the activity of rtks. Adenoid cystic carcinoma acc is an indolent salivary gland malignancy, characterized by t6. In a subset of accs, myb is replaced by the closely related mybl1 gene linked to nfib, or other fusion partners, resulting in gene fusions likely to have the same oncogenic properties as the myb. Overexpression of myb drives proliferation of cyld. The fusion gene fragment is predominantly myb, leading to the overexpression of myb mrna and a subsequent increase in protein expression level 12. Therapeutic targets adenoid cystic carcinoma research. The most frequent copy number alterations were losses of 12q12.
Transgenic models with inducible overexpression of the myb nfib fusion in the salivary gland compartment are in development. Keep informed and educated with the latest research. Genomic landscape of adenoid cystic carcinoma of the breast. Enjoy the combined purchasing power of all our members on great offers. All tumours were screened for the most common mybnfib fusion transcript variants, ie myb exon 14 fused to nfib exons 8a, 8c or 9, respectively, and myb exon 12 fused to nfib exon 9.
Analysis of myb expression and mybnfib gene fusions in adenoid cystic. Breast adenoid cystic carcinoma acc is a primary breast carcinoma that, like salivary gland acc, displays the t6. The firstround pcr was carried out using the myb primers myb697f5. Atr is a myb regulated gene and potential therapeutic target in. Proceedings of the national academy of sciences, october, 2009 cite this page. Role of myb and mybnfib fusions in salivary adenoid cystic carcinoma. Recurrent fusion of the vmyb avian myelobastosis viral oncogene homolog myb and nuclear factor ib nfib generates the mybnfib transcription factor, which has been detected in. Genomic imbalances and myb fusion in synchronous bilateral. The nfib gene is a part of the nfi gene complex that includes three other genes nfia, nfic and nfix. As an nfib member, you could save hundreds of dollars a year on car, home, condo or renters insurance with liberty mutual. Data from atlas, mitelman, cosmic fusion, fusion cancer, tcga fusion databases with official hugo symbols see references in chromosomal bands hmga2 12q14. Its cellular counterpart was subsequently isolated as c myb which has three functional domains dna binding domain, transactivation domain and negative regulatory domain. In salivary gland acc, in addition to the myb gene, alterations in mybl1, the gene closely related to myb, have been reported. Novel chromosomal rearrangements and break points at the t6.
The recent discovery of the myb nfib gene fusion in human accs has changed this outlook and stimulated new. Breakpoints in mybnfib and mybl1nfib fusion transcripts. Acc25 and 12 normal matched tissues using a customdesigned myb fusion gene panel containing myb 5. Frequent nfibassociated gene rearrangement in adenoid cystic. Analysis of myb expression and mybnfib gene fusions in. C schematic illustration depicting the myb and nfib genes as well as the mybnfib fusion gene coding exons are shown in darker red and blue and the resulting fusion protein. Novel mybl1 gene rearrangements with recurrent mybl1nfib. Pdf analysis of myb expression and mybnfib gene fusions in. Hmga2 nfib fusion strongly resembles the rearrangement between myb and nfib, as in both instances the aberration results in highly deregulated expression of dnabinding domains of the tf linked to. Mybactivated models for testing therapeutic agents in.
Atr is a myb regulated gene and potential therapeutic. To screen for the mybnfib gene fusion and the transcript formation, we conducted fish with bac clones for the myb gene green, rp11104d9, fig. Here we describe a new mechanism of activation of myb in human cancer involving gene fusion. The myb gene is a transcription factor that is very difficult to target.
While this might be partly explained by shortened survival due to the predominant phenotype of lethal bcell leukemia in. A nanostring probeset panel was designed targeting the junctions of three currently annotated mybnfib fusion genes as well as 5. Oncogenic signaling pathways were studied in cultured cells andor tumors from 15 acc patients. Pdf comprehensive analysis of the mybnfib gene fusion in. The mybnfib fusion drives proliferation of acc cells and is crucial for spherogenesis.
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