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1.
J Oral Pathol Med ; 46(9): 798-802, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28727172

ABSTRACT

BACKGROUND: Basal cell predominant salivary gland neoplasms can be difficult to separate histologically. One of the most aggressive of basaloid salivary gland neoplasms is adenoid cystic carcinoma. MYB expression by immunohistochemistry has been documented in adenoid cystic carcinoma. Some investigators have suggested that using this expression can help in establishing the diagnosis of adenoid cystic carcinoma. Utilizing tissue microarrays, we studied a group of basal cell adenocarcinomas and basal cell adenomas to determine: (i) whether either tumor expressed MYB and (ii) the frequency of any expression in either tumors. METHODS: Seventeen salivary gland basal cell adenocarcinomas and 30 salivary gland basal cell adenomas were used to construct microarrays. These tissue microarrays were used to assess for immunohistochemical MYB expression. RESULTS: Fifty-three percent (nine of 17) of salivary gland basal cell adenocarcinomas and 57% (17 of 30) of salivary gland basal cell adenomas showed MYB overexpression. For comparison, we studied 11 adenoid cystic carcinomas for MYB expression and found that 64% (seven of 11) overexpressed MYB. We found no relation to clinical course for basal adenomas or basal cell adenocarcinomas that overexpressed MYB vs those that did not. CONCLUSIONS: MYB expression does not help separate basal cell adenocarcinomas from basal cell adenomas, and our data suggest it does not differentiate between either of these neoplasms and adenoid cystic carcinoma.


Subject(s)
Adenocarcinoma/metabolism , Adenocarcinoma/pathology , Adenoma/metabolism , Adenoma/pathology , Oncogene Proteins v-myb/biosynthesis , Salivary Gland Neoplasms/metabolism , Salivary Gland Neoplasms/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Immunohistochemistry , Male , Middle Aged , Young Adult
2.
Am J Surg Pathol ; 41(10): 1422-1432, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28719465

ABSTRACT

Adenoid cystic carcinoma (ACC) is the second most common salivary gland malignancy and it has a high rate of recurrences and a poor long-term prognosis. Our aim was to assess the prognostic factors in ACC and study MYB-NFIB fusion and MYB protein expression in a large retrospective cohort of 135 patients with a median follow-up of 6.3 years. The 5- and 10-year local recurrence-free survival (RFS) rate of 94% and 78%, 5- and 10-year distant metastasis survival rate of 77% and 58%, and 5- and 10-year RFS of 66% and 44%. The following features were identified as adverse prognostic factors of RFS on univariate analysis: large tumor size, solid growth pattern, increased mitoses, positive margin, American Joint Committee on Cancer clinical staging, high-grade transformation, vascular invasion, nuclear atypia, open chromatin, prominent nucleoli, and tumor necrosis. However, on multivariate analysis, only increased mitoses (≥5/10 high-power fields), any solid growth pattern, and advanced American Joint Committee on Cancer TNM staging were independent adverse predictors for RFS. MYB immunoexpression and MYB-NFIB translocation were common findings in ACC, occurring in 72% and 59% of the tested ACCs, respectively. The sensitivity and specificity of MYB immunohistochemistry in detecting MYB-NFIB fusion was relatively low at 78% sensitivity and 50% specificity. The high prevalence of alterations leading to high expression of the MYB transcription factor family suggests that targeted approaches developed to suppress the expression of these oncogenic transcription factors and/or the transcriptional activity of these proteins would be a rational therapeutic approach to investigate in ACC.


Subject(s)
Carcinoma, Adenoid Cystic/pathology , Salivary Gland Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Carcinoma, Adenoid Cystic/chemistry , Carcinoma, Adenoid Cystic/metabolism , Female , Humans , Male , Middle Aged , NFI Transcription Factors/analysis , NFI Transcription Factors/biosynthesis , Oncogene Proteins v-myb/analysis , Oncogene Proteins v-myb/biosynthesis , Oncogene Proteins, Fusion/analysis , Oncogene Proteins, Fusion/biosynthesis , Prognosis , Protein Biosynthesis , Retrospective Studies , Salivary Gland Neoplasms/chemistry , Salivary Gland Neoplasms/metabolism , Young Adult
3.
Nat Genet ; 48(3): 265-72, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26829750

ABSTRACT

Translocation events are frequent in cancer and may create chimeric fusions or 'regulatory rearrangements' that drive oncogene overexpression. Here we identify super-enhancer translocations that drive overexpression of the oncogenic transcription factor MYB as a recurrent theme in adenoid cystic carcinoma (ACC). Whole-genome sequencing data and chromatin maps highlight distinct chromosomal rearrangements that juxtapose super-enhancers to the MYB locus. Chromosome conformation capture confirms that the translocated enhancers interact with the MYB promoter. Remarkably, MYB protein binds to the translocated enhancers, creating a positive feedback loop that sustains its expression. MYB also binds enhancers that drive different regulatory programs in alternate cell lineages in ACC, cooperating with TP63 in myoepithelial cells and a Notch program in luminal epithelial cells. Bromodomain inhibitors slow tumor growth in ACC primagraft models in vivo. Thus, our study identifies super-enhancer translocations that drive MYB expression and provides insight into downstream MYB functions in alternate ACC lineages.


Subject(s)
Carcinoma, Adenoid Cystic/genetics , Enhancer Elements, Genetic , Oncogene Proteins v-myb/biosynthesis , Translocation, Genetic , Carcinoma, Adenoid Cystic/pathology , Cell Line, Tumor , Cell Lineage/genetics , Chromatin/genetics , Gene Expression Regulation, Neoplastic , Humans , Oncogene Proteins v-myb/genetics , Oncogene Proteins, Fusion/biosynthesis , Oncogene Proteins, Fusion/genetics , Transcription Factors/biosynthesis , Tumor Suppressor Proteins/biosynthesis
4.
Nat Genet ; 48(3): 273-82, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26829751

ABSTRACT

Angiocentric gliomas are pediatric low-grade gliomas (PLGGs) without known recurrent genetic drivers. We performed genomic analysis of new and published data from 249 PLGGs, including 19 angiocentric gliomas. We identified MYB-QKI fusions as a specific and single candidate driver event in angiocentric gliomas. In vitro and in vivo functional studies show that MYB-QKI rearrangements promote tumorigenesis through three mechanisms: MYB activation by truncation, enhancer translocation driving aberrant MYB-QKI expression and hemizygous loss of the tumor suppressor QKI. To our knowledge, this represents the first example of a single driver rearrangement simultaneously transforming cells via three genetic and epigenetic mechanisms in a tumor.


Subject(s)
Glioma/genetics , Oncogene Proteins v-myb/genetics , Oncogene Proteins, Fusion/genetics , RNA-Binding Proteins/genetics , Carcinogenesis/genetics , Cell Line, Tumor , Child , Comparative Genomic Hybridization , Exome/genetics , Gene Expression Regulation, Neoplastic , Gene Rearrangement , Glioma/pathology , High-Throughput Nucleotide Sequencing , Humans , Mutation , Oncogene Proteins v-myb/biosynthesis , Oncogene Proteins, Fusion/biosynthesis , RNA-Binding Proteins/biosynthesis
5.
Indian J Pathol Microbiol ; 57(4): 611-3, 2014.
Article in English | MEDLINE | ID: mdl-25308019

ABSTRACT

Adenoid cystic carcinoma (ACC) is a rare tumor with characteristic histologic features. Staining with basal markers for estrogen receptor, progesterone receptor, and HER2 usually shows negative results. Immunohistochemical analysis of C-kit and MYB overexpression of the ACC also has been reported. We report two cases of ACC of the breast with C-kit and MYB overexpression that clinically confirm these previously reported characteristics and suggest that further molecular study of the expression of these two proteins can lead to future therapeutic strategies.


Subject(s)
Carcinoma, Adenoid Cystic , Oncogene Proteins v-myb/biosynthesis , Proto-Oncogene Proteins c-kit/biosynthesis , Triple Negative Breast Neoplasms , Aged , Biomarkers, Tumor , Breast/pathology , Cadherins/biosynthesis , Carcinoma, Adenoid Cystic/diagnostic imaging , Carcinoma, Adenoid Cystic/drug therapy , Carcinoma, Adenoid Cystic/surgery , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Female , Fluorouracil/therapeutic use , Humans , Immunohistochemistry , Mastectomy, Segmental , Middle Aged , Triple Negative Breast Neoplasms/diagnostic imaging , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/surgery , Ultrasonography
6.
Carcinogenesis ; 33(6): 1149-57, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22431717

ABSTRACT

Myb, a cellular progenitor of v-Myb oncogenes, is amplified in prostate cancer and exhibits greater amplification frequency in hormone-refractory disease. Here, we have investigated the functional significance of Myb in prostate cancer. Our studies demonstrate Myb expression in all prostate cancer cell lines (LNCaP, C4-2, PC3 and DU145) examined, whereas it is negligibly expressed in normal/benign prostate epithelial cells (RWPE1 and RWPE2). Notably, Myb is significantly upregulated, both at transcript (>60-fold) and protein (>15-fold) levels, in castration-resistant (C4-2) cells as compared with androgen-dependent (LNCaP) prostate cancer cells of the same genotypic lineage. Using loss and gain of function approaches, we demonstrate that Myb promotes and sustains cell cycle progression and survival under androgen-supplemented and -deprived conditions, respectively, through induction of cyclins (A1, D1 and E1), Bcl-xL and Bcl2 and downregulation of p27 and Bax. Interestingly, Myb overexpression is also associated with enhanced prostate-specific antigen expression. Furthermore, our data show a role of Myb in enhanced motility and invasion and decreased homotypic interactions of prostate cancer cells. Myb overexpression is also associated with actin reorganization leading to the formation of filopodia-like cellular protrusions. Immunoblot analyses demonstrate gain of mesenchymal and loss of epithelial markers and vice versa, in Myb-overexpressing LNCaP and -silenced C4-2 cells, respectively, indicating a role of Myb in epithelial to mesenchymal transition. Altogether, our studies provide first experimental evidence for a functional role of Myb in growth and malignant behavior of prostate cancer cells and suggest a novel mechanism for castration resistance.


Subject(s)
Androgens/metabolism , Oncogene Proteins v-myb/biosynthesis , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Androgens/deficiency , Apoptosis , Cell Cycle Checkpoints/genetics , Cell Line, Tumor , Cell Movement , Cell Proliferation , Cyclin A1/metabolism , Cyclin D1/metabolism , Cyclin E/metabolism , Epithelial-Mesenchymal Transition , Humans , Male , Neoplasm Invasiveness , Oncogene Proteins/metabolism , Oncogene Proteins v-myb/genetics , Orchiectomy , Proliferating Cell Nuclear Antigen/biosynthesis , Prostate/metabolism , Prostate/pathology , Prostate-Specific Antigen/biosynthesis , Prostatic Neoplasms/genetics , Prostatic Neoplasms/surgery , Pseudopodia , RNA Interference , RNA, Small Interfering , Transcription, Genetic , Up-Regulation , bcl-2-Associated X Protein/biosynthesis , bcl-Associated Death Protein/metabolism , bcl-X Protein/metabolism
7.
Mod Pathol ; 24(9): 1169-76, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21572406

ABSTRACT

Recent studies have shown that the recurrent t(6;9)(q22-23;p23-24) translocation in adenoid cystic carcinoma results in a novel fusion of the MYB proto-oncogene with the transcription factor gene NFIB. To determine the frequency of this finding, we used RT-PCR assays of the MYB and MYB-NFIB fusion transcripts, and immunohistochemistry for the MYB protein, to study adenoid cystic carcinomas and other epithelial tumors of the salivary glands, and head and neck region. MYB-NFIB fusion transcript was detected in 25 of 29 (86%) frozen adenoid cystic carcinoma tumor samples, and in 14 of 32 (44%) formalin-fixed paraffin-embedded adenoid cystic carcinoma tumor specimens. In contrast, the MYB-NFIB fusion was not expressed in non-adenoid cystic carcinoma neoplasms of the head and neck, confirming the high specificity of the MYB-NFIB fusion. Adenoid cystic carcinomas from various anatomic sites, including salivary gland, sinonasal cavity, tracheobronchial tree, larynx, breast, and vulva were repeatedly fusion-positive, indicating that adenoid cystic carcinomas located in different anatomic sites not only have important morphologic features in common, but also probably evolve through activation of the same molecular pathways. Studies of the expression of MYB revealed that 89% of the tumors, including both fusion-positive and fusion-negative cases, overexpressed MYB RNA. Similarly, 82% of adenoid cystic carcinomas stained positive for MYB protein, compared with 14% of non-adenoid cystic carcinoma neoplasms, indicating that MYB immunostaining may be useful for the diagnosis of adenoid cystic carcinoma, but that neoplasms sometimes in the differential diagnosis are also labeled. The latter are, however, fusion-negative. In summary, our studies show that MYB activation through gene fusion or other mechanisms is a major oncogenic event in adenoid cystic carcinoma occurring at various anatomic sites. In addition to being a diagnostically useful biomarker for adenoid cystic carcinoma, MYB and its downstream effectors are also novel potential therapeutic targets.


Subject(s)
Carcinoma, Adenoid Cystic/genetics , Oncogene Proteins v-myb/biosynthesis , Oncogene Proteins, Fusion/genetics , Salivary Gland Neoplasms/genetics , Adult , Aged , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Carcinoma, Adenoid Cystic/metabolism , Female , Genes, myb , Humans , Immunohistochemistry , Male , Middle Aged , Oncogene Proteins v-myb/genetics , Proto-Oncogene Mas , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Salivary Gland Neoplasms/metabolism , Young Adult
8.
Acta Neuropathol ; 120(6): 731-43, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21046410

ABSTRACT

Recent studies of genetic abnormalities in pediatric low-grade gliomas (LGGs) have focused on activation of the ERK/MAPK pathway by KIAA1549-BRAF gene fusions in the majority of pilocytic astrocytomas (PAs) and by rare mutations in elements of the pathway across histopathologically diverse LGGs. This study reports that MYB, an oncogene not previously implicated in gliomagenesis, is activated in a diverse subset of pediatric LGGs. The study cohort comprised 57 pediatric LGGs and a comparative cohort of 59 pediatric high-grade gliomas (HGGs). The LGG cohort included 34 PAs and 23 diffuse gliomas; fibrillary astrocytomas (n = 14), oligodendroglial tumors (n = 7), and angiocentric gliomas (n = 2). MYB copy number abnormalities were disclosed using Affymetrix 6.0 SNP arrays and confirmed using interphase fluorescence in situ hybridization. Novel MYB amplifications that upregulate MYB RNA and protein expression were demonstrated in 2/14 diffuse astrocytomas. In addition, focal deletion of the terminal region of MYB was seen in 1 of 2 angiocentric gliomas (AGs). Increased expression of MYB was demonstrated by quantitative RT-PCR and immunohistochemistry. MYB upregulation at the protein level was demonstrated in a proportion of diffuse LGGs (60%), pilocytic astrocytomas (41%), and HGGs (19%), but abnormalities at the genomic level were only a feature of diffuse gliomas. Our data suggest that MYB may have a role in a subset of pediatric gliomas, through a variety of mechanisms in addition to MYB amplification and deletion.


Subject(s)
Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Chromosome Aberrations , Glioma/genetics , Mutation/genetics , Oncogene Proteins v-myb/genetics , Up-Regulation/genetics , Adolescent , Age Distribution , Age Factors , Child , Child, Preschool , Cohort Studies , Female , Gene Amplification/genetics , Gene Deletion , Genetic Predisposition to Disease/genetics , Glioma/metabolism , Humans , Male , Oncogene Proteins v-myb/biosynthesis
9.
Leuk Res ; 34(3): 328-34, 2010 Mar.
Article in English | MEDLINE | ID: mdl-19615744

ABSTRACT

We investigated whether, in myelodysplastic syndromes (MDS), aberrant expression of miR-150/miR-221/miR-222 and their designated target mRNA molecules MYB, p27 and c-KIT may be involved in insufficient haematopoiesis. In a series of MDS (n=52), an aberrant increase of miR-150 was found only in MDS with associated del(5q) (n=9; p<0.01). The mRNA expression of transcription factor MYB, the designated target of miR-150, was shown to correlate inversely with the miR-150 level. Acute leukaemia evolving from MDS (n=11) showed significantly decreased levels of miR-221 but not miR-222. We conclude that inhibition of proliferation via over-expressed miR-150 might contribute to myelodysplastic haematopoiesis in MDS-del(5q).


Subject(s)
Gene Expression Regulation, Leukemic/genetics , MicroRNAs/genetics , Myelodysplastic Syndromes/genetics , Aged , Chromosome Aberrations , Female , Gene Expression Profiling , Humans , Male , Microsatellite Repeats/genetics , Myelodysplastic Syndromes/metabolism , Oncogene Proteins v-myb/biosynthesis , Proto-Oncogene Proteins c-kit/biosynthesis
10.
Cancer Res ; 60(19): 5323-8, 2000 Oct 01.
Article in English | MEDLINE | ID: mdl-11034064

ABSTRACT

Comparative genomic hybridization analysis has demonstrated that breast tumors from BRCA1 and BRCA2 germ-line mutation carriers contain a large number of chromosomal copy number gains and losses. A high regional copy number gain at 6q22-q24 was observed in one BRCA1 tumor, and fluorescence in situ hybridization analysis indicated a strong amplification of the MYB oncogene (15 copies of MYB compared with 1 copy of chromosome 6 centromere). Fluorescence in situ hybridization analysis revealed amplification of MYB in 5 (29%) of 17 BRCA1 breast tumors, whereas none of 8 BRCA2 tumors and 13 breast cancer cell lines, and only 2 of 100 sporadic breast tumors exhibited altered MYB copy numbers. Gene amplification resulted in mRNA overexpression as determined by Northern blot and cDNA microarray analysis, and protein overexpression by immunohistochemical staining. We conclude that MYB amplification is infrequent in sporadic breast cancer but common in breast tumors from BRCA1 mutation carriers, suggesting a role of this cell cycle regulator and transcription factor in the progression of some BRCA1 tumors. However, we cannot rule out the significance of other genes in the 6q22-q24 amplicon.


Subject(s)
Breast Neoplasms/genetics , Genes, BRCA1/genetics , Genes, myb/genetics , Blotting, Northern , Breast Neoplasms/metabolism , Chromosomes, Human, Pair 6/genetics , DNA, Complementary/genetics , DNA, Complementary/metabolism , DNA, Neoplasm/genetics , DNA, Neoplasm/metabolism , Gene Amplification , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Germ-Line Mutation , Humans , In Situ Hybridization, Fluorescence , Nucleic Acid Hybridization , Oncogene Proteins v-myb/biosynthesis , Oncogene Proteins v-myb/genetics , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Estrogen/physiology , Receptors, Progesterone/physiology
11.
Folia Biol (Praha) ; 45(3): 75-80, 1999.
Article in English | MEDLINE | ID: mdl-10730893

ABSTRACT

The distribution of RNA, total DNA and newly synthesized DNA within nucleoli-like structures in insect cells overexpressing v-myb oncogene was investigated. Three types of these structures which revealed interaction with anti-v-Myb oncoprotein antibody were found at the ultrastructural level. Specific staining by toluidine blue at pH 5.2 showed the presence of RNA in these nucleoli-like structures. To detect total DNA, the in situ terminal deoxynucleotidyl transferase-immunogold technique was used. In addition to an expected labeling of host condensed chromatin, the labeling of the three types of nucleoli-like structures differed from each other. While the compact (type I) and ring-shaped (type II) nucleoli-like structures were labeled only on their periphery and in the proximity of baculovirus particles that interacted with them, the structures with an appearance of nucleolonemas (type III) were labeled strongly. Incorporation of 5-bromo-2-deoxyuridine, in spite of a poor labeling of newly synthesized DNA, confirmed these results. We suggest that the nucleoli-like structures of type I and II are of nucleolar origin. The type III more likely represents virogenic stroma or viral DNA storage site.


Subject(s)
Antibodies, Monoclonal/immunology , Cell Nucleus/chemistry , DNA, Recombinant/analysis , Genes, myb , Genetic Vectors/genetics , Nucleopolyhedroviruses/genetics , Oncogene Proteins v-myb/biosynthesis , RNA, Messenger/analysis , Animals , Bromodeoxyuridine/metabolism , Cell Compartmentation , Cell Line , Cell Nucleolus/chemistry , Cell Nucleolus/ultrastructure , Cell Nucleus/ultrastructure , DNA Replication , Immunohistochemistry , Oncogene Proteins v-myb/immunology , Recombinant Fusion Proteins/biosynthesis , Spodoptera/cytology
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