Gene Summary

Gene:MYB; MYB proto-oncogene, transcription factor
Aliases: efg, Cmyb, c-myb, c-myb_CDS
Summary:This gene encodes a protein with three HTH DNA-binding domains that functions as a transcription regulator. This protein plays an essential role in the regulation of hematopoiesis. This gene may be aberrently expressed or rearranged or undergo translocation in leukemias and lymphomas, and is considered to be an oncogene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:transcriptional activator Myb
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

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Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Latest Publications: MYB (cancer-related)

Sakamoto K, Katayama R, Asaka R, et al.
Recurrent 8q24 rearrangement in blastic plasmacytoid dendritic cell neoplasm: association with immunoblastoid cytomorphology, MYC expression, and drug response.
Leukemia. 2018; 32(12):2590-2603 [PubMed] Related Publications
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare skin-tropic hematological malignancy of uncertain pathogenesis and poor prognosis. We examined 118 BPDCN cases for cytomorphology, MYC locus rearrangement, and MYC expression. Sixty-two (53%) and 41 (35%) cases showed the classic and immunoblastoid cytomorphology, respectively. Forty-one (38%) MYC

Zhao X, Zhang W, Ji W
YB-1 promotes laryngeal squamous cell carcinoma progression by inducing miR-155 expression via c-Myb.
Future Oncol. 2018; 14(16):1579-1589 [PubMed] Related Publications
AIM: In this study, we investigated the role of Y-box binding protein-1 (YB-1), c-Myb and miR-155 in human laryngeal squamous cell carcinoma (LSCC) progression.
MATERIALS & METHODS: Quantitative real-time PCR, western blot, MTT and Transwell were conducted to determine the expression and function of YB-1/miR-155 pathway. Univariate and multivariate analyses were used to determine the prognostic factors.
RESULTS: Expression of YB-1, c-Myb and miR-155 was higher in LSCC tissues. YB-1 promoted proliferation, invasiveness and migration of Hep-2 cells in vitro. Patients with higher YB-1 correlated with advanced T stage, poor differentiation and cervical metastasis. LSCC patients with high YB-1 expression showed poor overall survival.
CONCLUSION: YB-1 promotes LSCC progression by increasing miR-155 levels via c-Myb and acts as a prognostic factor.

Bishop JA, Westra WH
MYB Translocation Status in Salivary Gland Epithelial-Myoepithelial Carcinoma: Evaluation of Classic, Variant, and Hybrid Forms.
Am J Surg Pathol. 2018; 42(3):319-325 [PubMed] Free Access to Full Article Related Publications
Epithelial-myoepithelial carcinoma (EMC) is a malignant salivary gland neoplasm comprised of a biphasic arrangement of inner luminal ductal cells and outer myoepithelial cells. Adenoid cystic carcinoma (AdCC) is also a biphasic tumor comprised of ductal and myoepithelial cells, but these components tend to be arranged in a more cribriform pattern. The occurrence of "hybrid carcinomas" that show mixed patterns of EMC and AdCC raises questions about the relationship of these morphologically overlapping but clinically distinct tumors. AdCCs frequently harbor MYB-NFIB gene fusions. Mapping of EMCs (including hybrid forms with an AdCC component) for this fusion could help clarify the true nature of EMC as a distinct entity or simply as some variant form of AdCC. Twenty-nine cases of EMC were evaluated including 15 classic low-grade EMCs, 7 intermediate-grade EMCs, 2 EMCs with myoepithelial anaplasia, 1 EMC with high-grade transformation, and 4 hybrid EMCs with an AdCC component. Break apart fluorescence in situ hybridization for MYB was performed, as was MYB immunohistochemistry. For the hybrid carcinomas and those with high-grade transformation, the divergent tumor components were separately analyzed. A MYB translocation was identified in 5 of 28 (18%) tumors including 3 of 4 (75%) hybrid carcinomas and 2 of 7 (29%) intermediate-grade EMCs. For the positive hybrid carcinomas, the fusion was detected in both the EMC and AdCC components. The MYB fusion was not detected in any of the classic EMCs (0/15) or in any of the EMCs with myoepithelial anaplasia (0/2) or high-grade transformation (0/1). The fluorescence in situ hybridization assay was unsuccessful in 1 case. MYB immunostaining was seen in 5 of 5 fusion-positive cases, and also 9 of 23 fusion-negative tumors. Classic low-grade EMCs are genetically distinct from AdCCs in that they do not harbor MYB fusions. The presence of a MYB fusion in EMCs showing hybrid features of AdCC or exhibiting highly infiltrative growth points to a subset of these tumors that may well be true AdCCs masquerading as EMCs.

Ness SA
Editorial: Targeting MYB Oncogene Expression in Adenoid Cystic Carcinoma.
J Natl Cancer Inst. 2017; 109(9) [PubMed] Related Publications

Fujii K, Murase T, Beppu S, et al.
MYB, MYBL1, MYBL2 and NFIB gene alterations and MYC overexpression in salivary gland adenoid cystic carcinoma.
Histopathology. 2017; 71(5):823-834 [PubMed] Related Publications
AIMS: Adenoid cystic carcinoma (AdCC) is one of the most common salivary gland malignancies and the long-term prognosis is poor. In this study, we examined alterations of AdCC-associated genes, MYB, MYBL1, MYBL2 and NFIB, and their target molecules, including MYC. The results were correlated to clinicopathological profile of the patients.
METHODS AND RESULTS: Using paraffin tumour sections from 33 cases of salivary gland AdCC, we performed a detailed fluorescence in-situ hybridization (FISH) analysis for gene splits and fusions of MYB, MYBL1, MYBL2 and NFIB. We found that 29 of 33 (88%) AdCC cases showed gene splits in either MYB, MYBL1 or NFIB. None of the cases showed an MYBL2 gene alteration. AdCCs were divided genetically into six gene groups, MYB-NFIB (n = 16), MYB-X (n = 4), MYBL1-NFIB (n = 2), MYBL1-X (n = 1), NFIB-X (n = 6) and gene-split-negative (n = 4). AdCC patients showing the MYB or MYBL1 gene splits were associated with microscopically positive surgical margins (P = 0.0148) and overexpression of MYC (P = 0.0164). MYC expression was detected in both ductal and myoepithelial tumour cells, and MYC overexpression was associated with shorter disease-free survival of the patients (P = 0.0268).
CONCLUSIONS: The present study suggests that (1) nearly 90% of AdCCs may have gene alterations of either MYB, MYBL1 or NFIB, suggesting the diagnostic utility of the FISH assay, (2) MYB or MYBL1 gene splits may be associated with local aggressiveness of the tumours and overexpression of MYC, which is one of the oncogenic MYB/MYBL1 targets and (3) MYC overexpression may be a risk factor for disease-free survival in AdCC.

Dzikiewicz-Krawczyk A, Kok K, Slezak-Prochazka I, et al.
ZDHHC11 and ZDHHC11B are critical novel components of the oncogenic MYC-miR-150-MYB network in Burkitt lymphoma.
Leukemia. 2017; 31(6):1470-1473 [PubMed] Related Publications

Li Z, Abraham BJ, Berezovskaya A, et al.
APOBEC signature mutation generates an oncogenic enhancer that drives LMO1 expression in T-ALL.
Leukemia. 2017; 31(10):2057-2064 [PubMed] Free Access to Full Article Related Publications
Oncogenic driver mutations are those that provide a proliferative or survival advantage to neoplastic cells, resulting in clonal selection. Although most cancer-causing mutations have been detected in the protein-coding regions of the cancer genome; driver mutations have recently also been discovered within noncoding genomic sequences. Thus, a current challenge is to gain precise understanding of how these unique genomic elements function in cancer pathogenesis, while clarifying mechanisms of gene regulation and identifying new targets for therapeutic intervention. Here we report a C-to-T single nucleotide transition that occurs as a somatic mutation in noncoding sequences 4 kb upstream of the transcriptional start site of the LMO1 oncogene in primary samples from patients with T-cell acute lymphoblastic leukaemia. This single nucleotide alteration conforms to an APOBEC-like cytidine deaminase mutational signature, and generates a new binding site for the MYB transcription factor, leading to the formation of an aberrant transcriptional enhancer complex that drives high levels of expression of the LMO1 oncogene. Since APOBEC-signature mutations are common in a broad spectrum of human cancers, we suggest that noncoding nucleotide transitions such as the one described here may activate potent oncogenic enhancers not only in T-lymphoid cells but in other cell lineages as well.

Weissinger SE, Frick M, Möller P, et al.
Performance Testing of RREB1, MYB, and CCND1 Fluorescence In Situ Hybridization in Spindle-Cell and Desmoplastic Melanoma Argues for a Two-Step Test Algorithm.
Int J Surg Pathol. 2017; 25(2):148-157 [PubMed] Related Publications
BACKGROUND: Diagnostic confirmation of spindle-cell melanoma (SM) or desmoplastic melanoma (DM) as a melanoma can be challenging. In conventional melanoma (CM), a recently established fluorescence in situ hybridization (FISH) assay for RREB1, MYB, CCND1 can be helpful. Here, we determined the presence of RREB1, MYB, and CCND1 abnormalities in an SM/DM/mixed cohort.
METHODS: We assembled 49 cases and performed 3 separate hybridizations for RREB1/MYB/CCND1. We assessed clinical utility in diagnostically challenging cases and performed a cost and turnaround time analysis.
RESULTS: With regard to the diagnosis of melanoma, the FISH assay is 76% sensitive (n = 31/41 true positives melanomas) and 88% specific (n = 1/8 false positive desmoplastic nevi). The prevalence of abnormalities in DM is lower (12/19 cases, 63%; P = .03) than in SM (15/18 cases, 83%; P = .27), mixed (4 of 4 cases), or the reported sensitivity in CM (345/411 cases, 84%). The implied genetic differences in DM result in a higher false negative rate in DM (37%). Despite these limitations, when restricted to diagnostically challenging cases (n = 23), the FISH assay and, in particular, RREB1 was able to confirm melanoma in 70% (n = 16/23). Individual probe sensitivities ( RREB1 > MYB > CCND1) and a cost and turnaround time analysis argues for a 2-step test algorithm that reduces the economic impact of FISH testing considerably (~55%; n = 69 vs 123 hybridizations).
CONCLUSION: We propose a step-by-step genetic testing algorithm to support the diagnosis of melanoma in the setting of SM/DM and show that FISH testing is useful in diagnostically challenging cases.

Prieto-Granada CN, Zhang L, Antonescu CR, et al.
Primary cutaneous adenoid cystic carcinoma with MYB aberrations: report of three cases and comprehensive review of the literature.
J Cutan Pathol. 2017; 44(2):201-209 [PubMed] Free Access to Full Article Related Publications
Adenoid cystic carcinoma (ACC) is a relatively rare slow-growing and often-aggressive epithelial-myoepithelial neoplasm that arises in multiple organs including the skin. The t(6;9) (q22-23;p23-24) translocation, resulting in a MYB-NFIB gene fusion has been found in ACCs from the salivary glands and other organs. Recently, MYB aberrations occurring in a subset (40%) of primary cutaneous ACC (PCACC) examples was described. Herein, we report three additional cases of PCACC harboring MYB aberrations. The tumors presented in three males aged 43, 81 and 55 years old and affected the extremities in the first two patients and the scalp in the third one. None of the patients had history of prior or concurrent ACC elsewhere. Lesions exhibited the classic ACC morphology of nests of basaloid cells arranged in cribriform and adenoid patterns. Sentinel lymph node biopsy was performed in two cases with one case showing lymph node positivity. Fluorescence in situ hybridization with break-apart probes for MYB and NFIB loci revealed that two cases showed MYB rearrangements while one case showed loss of one MYB signal. None of the cases showed NFIB rearrangements. We contribute with three additional cases of PCACC exhibiting MYB aberrations, the apparent driving genetic abnormality in these tumors.

Zhang B, Yuan F, Liu J, et al.
Hsa-miR-495 acts as a tumor suppressor gene in glioma via the negative regulation of MYB.
Mol Med Rep. 2016; 14(1):977-82 [PubMed] Related Publications
MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at the post-transcriptional level. Previous studies have reported that there are causative links between the abnormal regulation of miRNAs and cancer development. Hsa‑miR‑495 has previously been demonstrated to be downregulated, and to function as a tumor suppressor, in numerous types of human cancer. However, the function and molecular mechanism of hsa‑miR‑495 in glioma remains unclear. In the current study, the expression and effects of hsa‑miR‑495 on glioma were evaluated. It was identified that the expression levels of hsa-miR-495 were downregulated in glioma tissues and cell lines. Furthermore, restoration of hsa-miR-495 inhibited glioma cell proliferation and invasion in vitro. Notably, a luciferase reporter assay revealed that hsa‑miR‑495 was able to directly target v‑myb avian myeloblastosis viral oncogene homolog (MYB) in glioma cells. In addition, an RNA interference assay indicated that MYB knockdown inhibited glioma cell proliferation and invasion in vitro. In conclusion, the results of the present study suggested that hsa‑miR‑495 may act as a tumor suppressor gene in glioma by directly inhibiting MYB expression, which may provide a novel therapeutic strategy for the treatment of glioma.

Broz M, Steiner P, Salzman R, et al.
The incidence of MYB gene breaks in adenoid cystic carcinoma of the salivary glands and its prognostic significance.
Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2016; 160(3):417-22 [PubMed] Related Publications
AIMS: To detect MYB gene breaks in adenoid cystic carcinoma (ACC) of the salivary glands and its correlation with prognosis and selected clinical parameters
METHODS: MYB gene break was detected by FISH assay in 23 adenoid cystic carcinomas using formalin-fixed paraffin-embedded blocks. The Kaplan-Meier survival analysis was used to estimate prognosis.
RESULTS: Fifteen of 23 evaluated tumours were MYB positive and 8 MYB negative. The 10-year cumulative survival, respectively disease free interval, was 60.0%, respectively 59.3%, in MYB positive patients and 88.5%, respectively 80.0%, in MYB negative patients (long rank test, P=0.23). There were no significant differences in age, gender, perineural invasion, the presence of hematogenic or nodal metastases or degree of histopathological grading between MYB positive and MYB negative patients.
CONCLUSION: A tendency to differences in the survival of patients with ACC, depending on their MYB status. MYB negative patients were predisposed to better prognosis.

Ferrarotto R, Heymach JV, Glisson BS
MYB-fusions and other potential actionable targets in adenoid cystic carcinoma.
Curr Opin Oncol. 2016; 28(3):195-200 [PubMed] Related Publications
PURPOSE OF REVIEW: Adenoid cystic carcinoma (ACC) is a rare cancer of the secretory glands, typically originating in the salivary glands of the head and neck. The impact of chemotherapy on survival is unclear and there are no standard-of-care treatments for patients with recurrent or metastatic disease. This article reviews recently completed and ongoing clinical trials for patients with ACC and describes recently identified potentially targetable genomic alterations in this orphan disease.
RECENT FINDINGS: In spite of an overall low mutational burden, genotyping of ACC samples has shed some light about the disease biology. In addition to the frequent translocations involving MYB or MYBL, recurrent alterations in genes involved in chromatin deregulation, FGF, PI3K, NOTCH1, and DNA damage repair pathways have been identified. Many of these genomic alterations are targetable and drug screening is ongoing in genotyped ACC patient-derived murine xenografts.
SUMMARY: Clinical studies with targeted agents in unselected ACC patients have not been promising thus far. The identification of potential driver oncogenes suggests that targeted therapy might be effective in molecularly-defined patient subgroups and merits investigation in future clinical studies.

Yang IP, Tsai HL, Huang CW, et al.
High blood sugar levels significantly impact the prognosis of colorectal cancer patients through down-regulation of microRNA-16 by targeting Myb and VEGFR2.
Oncotarget. 2016; 7(14):18837-50 [PubMed] Free Access to Full Article Related Publications
The high prevalence of type 2 diabetes mellitus in colorectal cancer patients is a crucial public health issue worldwide. The deregulation of microRNAs has been shown to be associated with the progression of CRC; however, the effects of high blood sugar levels on miR deregulation and, in turn, CRC remain unexplored. In this study, 520 CRC patients were classified into two groups according to their blood sugar levels (≧110 or <110 mg/dL). Clinicopathologic features, clinical outcomes, and serum miR-16 levels of the two groups were then analyzed, while cell cycles, cell proliferation, migration, and cellular miR-16 expression were investigated via D-(+)-glucose administration. Additionally, the target genes of miR-16 were identified. Through multivariate analysis, both the disease-free survival and overall survival of the CRC patients were found to be associated with the UICC stage, perineural invasion, and blood glucose levels (P < 0.05). Serum miR-16 levels were significantly lower in the high blood glucose patients than in the normal blood glucose patients (P = 0.0329). With D-(+)-glucose administration, the proliferation and migration of CRC cells in vitro increased remarkably (P < 0.05), while their accumulation in the G1 phase decreased significantly. Cellular miR-16 expression was suppressed by D-(+)-glucose administration. The expression levels of two target genes, Myb and VEGFR2, were affected significantly by miR-16, while glucose administration inhibited miR-16 expression and enhanced tumor cell proliferation and migration. Hyperglycemia can impact the clinical outcomes of CRC patients, likely by inhibiting miR-16 expression and the expression of its downstream genes Myb and VEGFR2.

Tichý M, Knopfová L, Jarkovský J, et al.
Overexpression of c-Myb is associated with suppression of distant metastases in colorectal carcinoma.
Tumour Biol. 2016; 37(8):10723-9 [PubMed] Related Publications
The MYB gene codes for the c-Myb transcription factor maintaining proliferation of colon epithelial progenitors, thus controlling colon development and homeostasis. This gene is overexpressed in early phases of colorectal cancer (CRC) tumorigenesis. The aim of this study was to examine the expression of c-Myb in CRC tissue samples both at the messenger RNA (mRNA) and protein levels and to evaluate their associations with clinicopathological characteristics in a group of 108 CRC patients. Statistically significant negative association was found between the frequency of the c-Myb-positive tumor cells assessed by immunohistochemistry and the presence of distant metastases (p < 0.01) but not tumor differentiation, tumor stage, lymph node involvement, vascular invasion, tumor localization, age, and gender of the patients. Although the c-Myb protein level in the tumor tissue correlated with its mRNA level, no significant association between MYB mRNA and any clinicopathological characteristics was observed. We conclude that albeit overexpression of c-Myb is considered as an important factor contributing to early phases of CRC tumorigenesis, it may later have negative effect on tumor cell dissemination as observed recently in breast cancer as well. Further studies are required to explain the role of c-Myb during formation of CRC distant metastases.

Gonda TJ, Ramsay RG
Adenoid Cystic Carcinoma Can Be Driven by MYB or MYBL1 Rearrangements: New Insights into MYB and Tumor Biology.
Cancer Discov. 2016; 6(2):125-7 [PubMed] Related Publications
A majority of adenoid cystic carcinomas (AdCC)-rare tumors of the salivary gland and some other organs-have recently been found to be driven by chromosomal translocations resulting in MYB-NFIB fusions. Brayer and colleagues and Mitani and colleagues have now reported that AdCCs can alternatively be driven by similar rearrangements involving a second MYB family gene, MYBL1, and that these two drivers act in remarkably similar ways.

Qaddoumi I, Orisme W, Wen J, et al.
Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology.
Acta Neuropathol. 2016; 131(6):833-45 [PubMed] Free Access to Full Article Related Publications
Low-grade neuroepithelial tumors (LGNTs) are diverse CNS tumors presenting in children and young adults, often with a history of epilepsy. While the genetic profiles of common LGNTs, such as the pilocytic astrocytoma and 'adult-type' diffuse gliomas, are largely established, those of uncommon LGNTs remain to be defined. In this study, we have used massively parallel sequencing and various targeted molecular genetic approaches to study alterations in 91 LGNTs, mostly from children but including young adult patients. These tumors comprise dysembryoplastic neuroepithelial tumors (DNETs; n = 22), diffuse oligodendroglial tumors (d-OTs; n = 20), diffuse astrocytomas (DAs; n = 17), angiocentric gliomas (n = 15), and gangliogliomas (n = 17). Most LGNTs (84 %) analyzed by whole-genome sequencing (WGS) were characterized by a single driver genetic alteration. Alterations of FGFR1 occurred frequently in LGNTs composed of oligodendrocyte-like cells, being present in 82 % of DNETs and 40 % of d-OTs. In contrast, a MYB-QKI fusion characterized almost all angiocentric gliomas (87 %), and MYB fusion genes were the most common genetic alteration in DAs (41 %). A BRAF:p.V600E mutation was present in 35 % of gangliogliomas and 18 % of DAs. Pathogenic alterations in FGFR1/2/3, BRAF, or MYB/MYBL1 occurred in 78 % of the series. Adult-type d-OTs with an IDH1/2 mutation occurred in four adolescents, the youngest aged 15 years at biopsy. Despite a detailed analysis, novel genetic alterations were limited to two fusion genes, EWSR1-PATZ1 and SLMAP-NTRK2, both in gangliogliomas. Alterations in BRAF, FGFR1, or MYB account for most pathogenic alterations in LGNTs, including pilocytic astrocytomas, and alignment of these genetic alterations and cytologic features across LGNTs has diagnostic implications. Additionally, therapeutic options based upon targeting the effects of these alterations are already in clinical trials.

Argyris PP, Wetzel SL, Greipp P, et al.
Clinical utility of myb rearrangement detection and p63/p40 immunophenotyping in the diagnosis of adenoid cystic carcinoma of minor salivary glands: a pilot study.
Oral Surg Oral Med Oral Pathol Oral Radiol. 2016; 121(3):282-9 [PubMed] Related Publications
OBJECTIVES: MYB rearrangement is observed in approximately 28% to 86% of adenoid cystic carcinomas (ACCs). Also, ACC features a p63+/p40+ immunophenotype in greater than 90% of cases, compared with p63+/p40- polymorphous low-grade adenocarcinoma (PLGA). Our aim was to investigate the incidence of (1) MYB rearrangement and (2) p63/p40 immunoreactivity in ACC and PLGA of minor salivary glands (MSGs).
STUDY DESIGN: Seven cases of ACC as well as five of PLGA were evaluated by using a MYB (6 q23.3) break-apart fluorescence in situ hybridization (FISH) probe. In addition, all cases were immunohistochemically stained with p63 and p40 antibodies.
RESULTS: All five successfully hybridized ACCs featured MYB rearrangement, whereas PLGAs did not show MYB rearrangement. Interestingly, one case of PLGA demonstrated a single intact copy of MYB in greater than 88% of the neoplastic cells. All ACCs exhibited consistent p63+/p40+ staining, whereas PLGAs demonstrated a p63+/p40- immunophenotype.
CONCLUSIONS: (1) MYB rearrangement is encountered in ACCs but not PLGAs of MSGs; (2) MYB aberrations, for example, monosomy or deletion, can be seen in PLGAs; (3) combined p63/p40 immunostaining can be used to differentiate ACC from PLGA in incisionally biopsied specimens; and (4) performance of either FISH or p63/p40 immunohistochemistry is expected to be able to confirm the diagnosis of ACC or PLGA in small intraoral biopsies, since both techniques appeared to be diagnostically accurate in this pilot study.

Tian Z, Li L, Zhang CY, et al.
Differences in MYB expression and gene abnormalities further confirm that salivary cribriform basal cell tumors and adenoid cystic carcinoma are two distinct tumor entities.
J Oral Pathol Med. 2016; 45(9):698-703 [PubMed] Related Publications
BACKGROUND: In practices, some cases of salivary basal cell tumors that consist mainly of cribriform growth pattern are difficult to differentiate from adenoid cystic carcinoma (AdCC). Identification of reliable molecular biomarkers for the differential diagnosis between them is required.
METHODS: Twenty-two cases of cribriform salivary basal cell tumors (at least 10% cribriform pattern present in each tumor) comprising 18 cases of basal cell adenoma (BCA) and four cases of basal cell adenocarcinoma (BcAC) were collected between 1985 and 2008. Twenty cases of cribriform AdCC were retrieved from our archives. MYB protein expression and gene abnormalities were detected in all cases by immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) analyses, respectively.
RESULTS: Neither MYB protein nor split genes were detected in any of the cases of cribriform basal cell tumors, while 55% (11/20) of cases of cribriform AdCC had MYB protein expression. High MYB expression was detected in 81.8% (9/11) cases, while low expression was found in the remaining cases. FISH analysis indicated that nine AdCC tumors with high MYB protein expression were split gene-positive, while MYB gene splitting was not detected in the 11 cases with low or absent MYB protein expression.
CONCLUSION: The molecular changes in AdCC differ from those associated with cribriform basal cell tumors, which further confirms that cribriform basal cell tumors and AdCC are two distinct tumor entities. Simultaneous detection of MYB protein expression and the associated molecular changes could be beneficial in differentiating salivary cribriform basal cell tumors from AdCC.

Srivastava SK, Bhardwaj A, Arora S, et al.
MYB is a novel regulator of pancreatic tumour growth and metastasis.
Br J Cancer. 2015; 113(12):1694-703 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: MYB encodes for a transcription factor regulating the expression of a wide array of genes involved in cellular functions. It is reported to be amplified in a sub-set of pancreatic cancer (PC) cases; however, its pathobiological association has remained unclear thus far.
METHODS: Expression of MYB and other cellular proteins was analysed by immunoblot or qRT-PCR analyses. MYB was stably overexpressed in non-expressing (BxPC3) and silenced in highly expressing (MiaPaCa and Panc1) PC cells. Effect on growth was analysed by automated cell counting at 24-h interval. Cell-cycle progression and apoptotic indices of PC cells with altered MYB expression were measured through flow cytometry upon staining with respective biomarkers. Cell motility/invasion was examined in a Boyden's chamber assay using non-coated or Matrigel-coated membranes. Effect on tumorigenicity and metastatic potential was examined by non-invasive imaging and through end-point measurements of luciferase-tagged MYB-altered PC implanted in the pancreas of nude mice.
RESULTS: MYB was aberrantly expressed in all malignant cases of pancreas, whereas remained undetectable in normal pancreas. All the tested established PC cell lines except BxPC3 also exhibited MYB expression. Forced expression of MYB in BxPC3 cells promoted their growth, cell-cycle progression, survival and malignant behaviour, whereas its silencing in MiaPaCa and Panc1 cells produced converse effects. More importantly, ectopic MYB expression was sufficient to confer tumorigenic and metastatic capabilities to non-tumorigenic BxPC3 cells, while its silencing resulted in significant loss of the same in MYB-overexpressing cells as demonstrated in orthotopic mouse model. We also identified several MYB-regulated genes in PC cells that might potentially mediate its effect on tumour growth and metastasis.
CONCLUSIONS: MYB is aberrantly overexpressed in PC cells and acts as a key determinant of pancreatic tumour growth and metastasis.

Giotopoulos G, van der Weyden L, Osaki H, et al.
A novel mouse model identifies cooperating mutations and therapeutic targets critical for chronic myeloid leukemia progression.
J Exp Med. 2015; 212(10):1551-69 [PubMed] Free Access to Full Article Related Publications
The introduction of highly selective ABL-tyrosine kinase inhibitors (TKIs) has revolutionized therapy for chronic myeloid leukemia (CML). However, TKIs are only efficacious in the chronic phase of the disease and effective therapies for TKI-refractory CML, or after progression to blast crisis (BC), are lacking. Whereas the chronic phase of CML is dependent on BCR-ABL, additional mutations are required for progression to BC. However, the identity of these mutations and the pathways they affect are poorly understood, hampering our ability to identify therapeutic targets and improve outcomes. Here, we describe a novel mouse model that allows identification of mechanisms of BC progression in an unbiased and tractable manner, using transposon-based insertional mutagenesis on the background of chronic phase CML. Our BC model is the first to faithfully recapitulate the phenotype, cellular and molecular biology of human CML progression. We report a heterogeneous and unique pattern of insertions identifying known and novel candidate genes and demonstrate that these pathways drive disease progression and provide potential targets for novel therapeutic strategies. Our model greatly informs the biology of CML progression and provides a potent resource for the development of candidate therapies to improve the dismal outcomes in this highly aggressive disease.

Martelotto LG, De Filippo MR, Ng CK, et al.
Genomic landscape of adenoid cystic carcinoma of the breast.
J Pathol. 2015; 237(2):179-89 [PubMed] Free Access to Full Article Related Publications
Adenoid cystic carcinoma (AdCC) is a rare type of triple-negative breast cancer (TNBC) characterized by the presence of the MYB-NFIB fusion gene. The molecular underpinning of breast AdCCs other than the MYB-NFIB fusion gene remains largely unexplored. Here we sought to define the repertoire of somatic genetic alterations of breast AdCCs. We performed whole-exome sequencing, followed by orthogonal validation, of 12 breast AdCCs to determine the landscape of somatic mutations and gene copy number alterations. Fluorescence in situ hybridization and reverse-transcription PCR were used to define the presence of MYB gene rearrangements and MYB-NFIB chimeric transcripts. Unlike common forms of TNBC, we found that AdCCs have a low mutation rate (0.27 non-silent mutations/Mb), lack mutations in TP53 and PIK3CA and display a heterogeneous constellation of known cancer genes affected by somatic mutations, including MYB, BRAF, FBXW7, SMARCA5, SF3B1 and FGFR2. MYB and TLN2 were affected by somatic mutations in two cases each. Akin to salivary gland AdCCs, breast AdCCs were found to harbour mutations targeting chromatin remodelling, cell adhesion, RNA biology, ubiquitination and canonical signalling pathway genes. We observed that, although breast AdCCs had rather simple genomes, they likely display intra-tumour genetic heterogeneity at diagnosis. Taken together, these findings demonstrate that the mutational burden and mutational repertoire of breast AdCCs are more similar to those of salivary gland AdCCs than to those of other types of TNBCs, emphasizing the importance of histological subtyping of TNBCs. Furthermore, our data provide direct evidence that AdCCs harbour a distinctive mutational landscape and genomic structure, irrespective of the disease site of origin.

Bishop JA, Yonescu R, Epstein JI, Westra WH
A subset of prostatic basal cell carcinomas harbor the MYB rearrangement of adenoid cystic carcinoma.
Hum Pathol. 2015; 46(8):1204-8 [PubMed] Related Publications
Adenoid cystic carcinoma (ACC) is a basaloid tumor consisting of myoepithelial and ductal cells typically arranged in a cribriform pattern. Adenoid cystic carcinoma is generally regarded as a form of salivary gland carcinoma, but it can arise from sites unassociated with salivary tissue. A rare form of prostate carcinoma exhibits ACC-like features; it is no longer regarded as a true ACC but rather as prostatic basal cell carcinoma (PBCC) and within the spectrum of basaloid prostatic proliferations. True ACCs often harbor MYB translocations resulting in the MYB-NFIB fusion protein. MYB analysis could clarify the true nature of prostatic carcinomas that exhibit ACC features and thus help refine the classification of prostatic basaloid proliferations. Twelve PBCCs were identified from the pathology consultation files of Johns Hopkins Hospital. The histopathologic features were reviewed, and break-apart fluorescence in situ hybridization for MYB was performed. All 12 cases exhibited prominent basaloid histology. Four were purely solid, 7 exhibited a cribriform pattern reminiscent of salivary ACC, and 1 had a mixed pattern. The MYB rearrangement was detected in 2 (29%) of 7 ACC-like carcinomas but in none (0%) of the 5 PBCCs with a prominent solid pattern. True ACCs can arise in the prostate as is evidenced by the presence of the characteristic MYB rearrangement. When dealing with malignant basaloid proliferations in the prostate, recommendations to consolidate ACCs with other tumor types may need to be reassessed, particularly in light of the rapidly advancing field of biologic therapy where the identification of tumor-specific genetic alterations presents novel therapeutic targets.

North JP, McCalmont TH, Fehr A, et al.
Detection of MYB Alterations and Other Immunohistochemical Markers in Primary Cutaneous Adenoid Cystic Carcinoma.
Am J Surg Pathol. 2015; 39(10):1347-56 [PubMed] Related Publications
Adenoid cystic carcinoma (ACC) can arise in several organs, and prognosis is highly dependent on the primary tumor site. Primary cutaneous ACC has an excellent prognosis compared with salivary or lacrimal ACC. Activation of MYB by gene fusion or other mechanisms has been found in salivary, breast, and lacrimal ACCs but has not been described in cutaneous ACC. We analyzed the histopathologic and immunohistochemical features of 19 primary cutaneous ACCs, 2 periorbital ACCs, and 12 salivary gland ACCs and assessed for MYB activation in primary cutaneous ACC by immunohistochemistry and molecular methods. The presence of perineural invasion differed significantly among ACCs of various sites (83% salivary, 50% eyelid, 11% skin, P=0.0002). Over 90% of all ACCs were grade 1 or 2 and exhibited diffuse (>50%) positivity with CD117, SOX-10, and smooth muscle actin immunostains. CK15 and vimentin showed diffuse positivity in 36% and 57% of cutaneous ACCs, respectively, and were negative or only focally positive in all salivary ACCs (P=0.04 and 0.002). Six of the 11 cutaneous and periorbital ACCs tested with reverse transcriptase polymerase chain reaction and/or fluorescence in situ hybridization had MYB rearrangements including 2 cases that expressed MYB-NFIB fusion transcripts. Diffuse expression of MYB protein assessed by immunostaining was present in 8 of 9 cutaneous ACCs, including cases both with and without MYB rearrangements. These results indicate that cutaneous ACCs possess the same types of MYB alterations as ACCs of other anatomic sites. Vimentin and CK15 appear to have some discriminatory value in differentiating between primary cutaneous and salivary gland ACCs.

Tapper W, Jones AV, Kralovics R, et al.
Genetic variation at MECOM, TERT, JAK2 and HBS1L-MYB predisposes to myeloproliferative neoplasms.
Nat Commun. 2015; 6:6691 [PubMed] Free Access to Full Article Related Publications
Clonal proliferation in myeloproliferative neoplasms (MPN) is driven by somatic mutations in JAK2, CALR or MPL, but the contribution of inherited factors is poorly characterized. Using a three-stage genome-wide association study of 3,437 MPN cases and 10,083 controls, we identify two SNPs with genome-wide significance in JAK2(V617F)-negative MPN: rs12339666 (JAK2; meta-analysis P=1.27 × 10(-10)) and rs2201862 (MECOM; meta-analysis P=1.96 × 10(-9)). Two additional SNPs, rs2736100 (TERT) and rs9376092 (HBS1L/MYB), achieve genome-wide significance when including JAK2(V617F)-positive cases. rs9376092 has a stronger effect in JAK2(V617F)-negative cases with CALR and/or MPL mutations (Breslow-Day P=4.5 × 10(-7)), whereas in JAK2(V617F)-positive cases rs9376092 associates with essential thrombocythemia (ET) rather than polycythemia vera (allelic χ(2) P=7.3 × 10(-7)). Reduced MYB expression, previously linked to development of an ET-like disease in model systems, associates with rs9376092 in normal myeloid cells. These findings demonstrate that multiple germline variants predispose to MPN and link constitutional differences in MYB expression to disease phenotype.

Gao R, Cao C, Zhang M, et al.
A unifying gene signature for adenoid cystic cancer identifies parallel MYB-dependent and MYB-independent therapeutic targets.
Oncotarget. 2014; 5(24):12528-42 [PubMed] Free Access to Full Article Related Publications
MYB activation is proposed to underlie development of adenoid cystic cancer (ACC), an aggressive salivary gland tumor with no effective systemic treatments. To discover druggable targets for ACC, we performed global mRNA/miRNA analyses of 12 ACC with matched normal tissues, and compared these data with 14 mucoepidermoid carcinomas (MEC) and 11 salivary adenocarcinomas (ADC). We detected a unique ACC gene signature of 1160 mRNAs and 22 miRNAs. MYB was the top-scoring gene (18-fold induction), however we observed the same signature in ACC without detectable MYB gene rearrangements. We also found 4 ACC tumors (1 among our 12 cases and 3 from public databases) with negligible MYB expression that retained the same ACC mRNA signature including over-expression of extracellular matrix (ECM) genes. Integration of this signature with somatic mutational analyses suggests that NOTCH1 and RUNX1 participate with MYB to activate ECM elements including the VCAN/HAPLN1 complex. We observed that forced MYB-NFIB expression in human salivary gland cells alters cell morphology and cell adhesion in vitro and depletion of VCAN blocked tumor cell growth of a short-term ACC tumor culture. In summary, we identified a unique ACC signature with parallel MYB-dependent and independent biomarkers and identified VCAN/HAPLN1 complexes as a potential target.

Dillon PM, Chakraborty S, Moskaluk CA, et al.
Adenoid cystic carcinoma: A review of recent advances, molecular targets, and clinical trials.
Head Neck. 2016; 38(4):620-7 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Adenoid cystic carcinoma (ACC) is a rare tumor of secretory glands. In this study, recent advances in molecular characterization and in therapeutics are reviewed.
METHODS: A search of articles in PubMed and of abstracts from national meetings was performed regarding ACC.
RESULTS: Recent genetic analyses found that recurrent chromosome 6:9 translocations in ACC generate an MYB:NFIB gene fusion resulting in overexpression of the MYB oncoprotein. Several other frequent mutations are recently published that may be relevant for drug development. Several trials of targeted drugs are reviewed. Some agents delay tumor progression, but tumor responses remain rare.
CONCLUSION: ACCs have a characteristic chromosomal translocation, but also frequently pick up additional mutations. Clinical research is limited by the rarity and slow growth of ACC. Several ongoing trials are testing agents that inhibit fibroblast growth factor receptor signaling or other signaling pathways. Novel treatments based on the recently sequenced tumor genome are under development.

Sanghvi VR, Mavrakis KJ, Van der Meulen J, et al.
Characterization of a set of tumor suppressor microRNAs in T cell acute lymphoblastic leukemia.
Sci Signal. 2014; 7(352):ra111 [PubMed] Free Access to Full Article Related Publications
The posttranscriptional control of gene expression by microRNAs (miRNAs) is highly redundant, and compensatory effects limit the consequences of the inactivation of individual miRNAs. This implies that only a few miRNAs can function as effective tumor suppressors. It is also the basis of our strategy to define functionally relevant miRNA target genes that are not under redundant control by other miRNAs. We identified a functionally interconnected group of miRNAs that exhibited a reduced abundance in leukemia cells from patients with T cell acute lymphoblastic leukemia (T-ALL). To pinpoint relevant target genes, we applied a machine learning approach to eliminate genes that were subject to redundant miRNA-mediated control and to identify those genes that were exclusively targeted by tumor-suppressive miRNAs. This strategy revealed the convergence of a small group of tumor suppressor miRNAs on the Myb oncogene, as well as their effects on HBP1, which encodes a transcription factor. The expression of both genes was increased in T-ALL patient samples, and each gene promoted the progression of T-ALL in mice. Hence, our systematic analysis of tumor suppressor miRNA action identified a widespread mechanism of oncogene activation in T-ALL.

Magro CM, Abraham RM, Guo R, et al.
Deep penetrating nevus-like borderline tumors: A unique subset of ambiguous melanocytic tumors with malignant potential and normal cytogenetics.
Eur J Dermatol. 2014 Sep-Oct; 24(5):594-602 [PubMed] Related Publications
BACKGROUND: Deep penetrating nevi (DPN) are a relatively uncommon subtype of melanocytic nevi. A small subset of these lesions exhibit atypical features (cytologic and architectural atypia, mitotic activity) seen in melanoma. These lesions we term the deep penetrating nevus-like borderline tumor. Unequivocal melanomas can show overlapping morphologic features of DPN, which have been termed plexiform melanomas.
PATIENTS AND METHODS: 40 cases of DPN-like borderline tumor were identified along with 6 cases of plexiform melanoma. Clinical follow up was obtained, along with cytogenetic analysis in the form of fluorescent in situ hybridization (FISH) and/or comparative genomic hybridization (CGH).
RESULTS: The DPN-like borderline tumor cases included 24 females and 16 males. Of sentinel lymph node biopsies performed, 1/3 of cases showed lymph node involvement. All patients where an aggressive clinical approach was adopted remain free of disease. All 6 DPN-like borderline tumor cases tested by CGH showed normal cytogenetics, as did 7 of 9 cases tested by FISH. Of the plexiform melanomas, 4/6 patients died of disease. In 3 cases there was morphologic progression from a DPN-like borderline tumor to overt melanoma. In one case of progression, cytogenetics was normal in the DPN-like borderline tumor and then abnormal in the progressed melanoma.
CONCLUSION: DPN-like borderline tumors are melanocytic tumors associated with a high incidence of regional lymph node disease and exhibiting the potential for melanoma progression despite a normal cytogenetic profile. Patients with these lesions should be aggressively managed, with at least complete re-excision and consideration of sentinel node biopsy, regardless of cytogenetic data.

Costa AF, Altemani A, García-Inclán C, et al.
Analysis of MYB oncogene in transformed adenoid cystic carcinomas reveals distinct pathways of tumor progression.
Lab Invest. 2014; 94(6):692-702 [PubMed] Related Publications
Adenoid cystic carcinomas can occasionally undergo dedifferentiation, a phenomenon also referred to as high-grade transformation. However, cases of adenoid cystic carcinomas have been described showing transformation to adenocarcinomas that are not poorly differentiated, indicating that high-grade transformation may not necessarily reflect a more advanced stage of tumor progression, but rather a transformation to another histological form, which may encompass a wide spectrum of carcinomas in terms of aggressiveness. The aim of this study was to gain more insight in the biology of this pathological phenomenon by means of genetic profiling of both histological components. Using microarray comparative genomic hybridization, we compared the genome-wide DNA copy-number changes of the conventional and transformed area of eight adenoid cystic carcinomas with high-grade transformation, comprising four with transformation into moderately differentiated adenocarcinomas and four into poorly differentiated carcinomas. In general, the poorly differentiated carcinoma cases showed a higher total number of copy-number changes than the moderately differentiated adenocarcinoma cases, and this correlated with a worse clinical course. Special attention was given to chromosomal translocation and protein expression of MYB, recently being considered to be an early and major oncogenic event in adenoid cystic carcinomas. Our data showed that the process of high-grade transformation is not always accompanied by an accumulation of genetic alterations; both conventional and transformed components harbored unique genetic alterations, which indicate a parallel progression. Our data further demonstrated that the MYB/NFIB translocation is not necessarily an early event or fundamental for the progression to adenoid cystic carcinoma with high-grade transformation.

Yu L, Ding GF, He C, et al.
MicroRNA-424 is down-regulated in hepatocellular carcinoma and suppresses cell migration and invasion through c-Myb.
PLoS One. 2014; 9(3):e91661 [PubMed] Free Access to Full Article Related Publications
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. MicroRNAs (miRNAs) are important regulators of multiple cellular processes, and the aberrant miRNAs expressions have been observed in different types of cancer including HCC. Their pathysiologic role and their relevance to tumorigenesis are still largely unknown. In this study, we demonstrated the down-regulation of miR-424 in HCC cell lines and tissues by quantitative RT-PCR analyses. Overexpression of miR-424 reduced the HCC cell prolifetation, migration, and invasion. Conversely, inhibiton of miR-424 expression significantly accelerated the cell proliferation, migration, and invasion. In addition, we further identified c-Myb as a functional downstream target of miR-424 by directly targeting the 3'UTR of c-Myb. Furthermore, overexpression of c-Myb impaired miR-424-induced inhibition of proliferation and invasion in HCC cells. Our results demonstrated that miR-424 was involved in tumorigenesis of HCC at least in part by suppression of c-Myb.

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