EGAGenomicsBirgit Knoechelhttps://ega-archive.org/dacs/EGAC00001000376EGAEGA DAC EGAC00001000376EGABirgit_Knoechel@dfci.harvard.eduTranslocation 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.An oncogenic MYB feedback loop drives alternate cell fates in adenoid cystic carcinoma.Drier Yotam Y, Cotton Matthew J MJ, Williamson Kaylyn E KE, Gillespie Shawn M SM, Ryan Russell J H RJ, Kluk Michael J MJ, Carey Christopher D CD, Rodig Scott J SJ, Sholl Lynette M LM, Afrogheh Amir H AH, Faquin William C WC, Queimado Lurdes L, Qi Jun J, Wick Michael J MJ, El-Naggar Adel K AK, Bradner James E JE, Moskaluk Christopher A CA, Aster Jon C JC, Knoechel Birgit B, Bernstein Bradley E BEc-myb_CDS, Carcinoma, dTAF[[II]]230, TAF[[II]]250, d230, xmyb, Dm Myb, myb1, Dm-myb, Adenocystic, TAF200, l(3)84Ab, dTAFII250, MYB, BG:DS00004.13, TAFII-250, TAF250/230, EfW1, dMyb, Cell, l(1)XVI, dTAF230, dmTAF[[II]]230, c-Myb, TAFII250, Dm myb, Adenocystic Carcinoma, Adenoid Cystic, dmTAF1, Taf230, Cystic Carcinoma, p230, TAF[[II]]250/230, Cystic Carcinomas, TFIID, Cmyb, Adenocystic Carcinomas, myb, DmelCG9045, DmMyb, DmMYB, TAF250, Carcinomas, Taf[[II]]250, Cylindromas, Adenoid, Taf200, c-myb, dTAF[[II]]250, TAF[[II]]230, Drives, TFIID TAF250, cel, cell, Dmyb, Taf1p, TAF[II]250, CG17603, Adenoid Cystic Carcinomas., TAF[[II]], cmyb, dmMYB, ACC, dTAF250, cylindroma, DmelCG17603, AI550390, efg, Taf250, cribriform carcinoma, CG9045, SR3-5, p85, Dm-Myb, Adenoid Cystic Carcinoma, Cylindroma, DMyb, M16449, Feedbacks, TAF, D-myb, dmyb, TAF230, TAF1fbwd4, acc, d-tacc, scalp defect, l(2)04454, DmelCG1772, dac, CIB1, scalp defect congenital, CG9765, p21[dacapo], dactylin, ACCA, E130112M23Rik, cdi4, 1-Aminocyclopropane-1-carboxylic acid, DmelCG9765, TACC, dactylyn, congenital, p21, CG1772, FBWD4, Cdi4, CDI4, CG8723, p27, DTACC, Decapo, FBgn0043811, CG11198, dtacc, DmelCG11198, shsf3, D-tacc, shfm3, aplasia cutis congenita, dACC, study., E(Sev-CycE)2B, Fbw4, FBW4, dTACC, ACAC, TACCdm, D-TACC, ACACAD, ACC, Dach, CDKN2B, SHFM3, nonsyndromic, BMS1L, Dac, DAC, p27[Dap], DmACC, congenital defect of skull and scalp, aplasia cutis congenita nonsyndromic, dacapo/cyclin-dependent kinase interactor 4, AI182278, ACC1, Dap, CES5A1, P15, fbw4, SHSF3c-myb_CDS, d-tacc, Phenylethylbarbiturate, T-cell leukemia, Dm Myb, xnotch, Epithelial Cell, postnatal development, AGL4, Adenocystic, growth and development, MYB, protein, Tumor, Glandular, l(1)XVI, ACCA, TP63, c-Myb, DmelCG9765, Dm myb, Tp73l, NOTCH, Phenylethylbarbituric Acid, congenital, RNA polymerase II distal enhancer sequence-specific DNA binding transcription factor activity, B(p51B), TP73L, 2, Adenocystic Carcinomas, 6-trione, DTACC, 4, slow, myb, protein aggregate, notch, Ket, KET, Chromatins, TRic, c-myb, dtacc, P51/P63, OFC8, Genomes, B(p51A), p73H, CUSP, Phenylbarbital, aplasia cutis congenita, F10N7_150, chromatid, Adenomatous Epithelial, Ax, 5-ethyl-5-phenyl-2, dTACC, Cell Lineages, RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity, ket, ACACAD, ACC, high frequency, BMS1L, AI550390, notch1-a, malignant neoplasm, congenital defect of skull and scalp, aplasia cutis congenita nonsyndromic, CG9045, co, chromosome scaffold, Xotch, AGAMOUS-like 4, 6(1H, Malignancies, zinc ion regulated proximal promoter sequence-specific DNA binding, sequence-specific transcription regulatory region DNA binding RNA polymerase II transcription factor recruiting transcription factor activity, 3H, TL, Transformation-related protein 63, NECD, EG:140G11.1, TRANSCRIPTION FACTOR, Tp63, l(1)N, Tumors, RNA polymerase II distal enhancer sequence-specific binding, swb, acc, nuclear chromatin, Transitional Epithelial Cell, RNA polymerase II core promoter proximal region sequence-specific binding, Carcinoma, xmyb, myb1, Trp53rp1, Chp, Co, CG11198., Maps, Adenomatous, Adenoid Cystic Carcinomas, CG9765, Squamous, metal ion regulated sequence-specific DNA binding RNA polymerase II transcription factor activity, Transitional Epithelial, Programs, Cct1, Benign, Adenoid Cystic, shd, P51|P63, p73L, sequence-specific distal enhancer binding RNA polymerase II transcription factor activity, DmelCG9045, fa, FBgn0043811, c-cpn, Carcinomas, F14P3.4, Cylindromas, Adenomatous Epithelial Cell, Adenoid, xnotch1, Acid, Adenomatous Epithelial Cells, Squamous Cell, Factors, Drives, growth pattern, non-developmental growth, EEC3, F14P3_4, 5-Ethyl-5-phenyl-pyrimidine-2, Benign Neoplasms, 5H)-trione, whole genome, Transcription factor, RHS, cmyb, Malignant Neoplasms, cylindroma, nonsyndromic, 5-ethyl-5-phenylpyrimidine-2, Monosodium Salt Phenobarbital, P73l, DmACC, Chromosome, clone 1.12, Dm-Myb, p40, Cells, copper ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, Ccta, LMS, notch-1, Feedbacks, TAN1, Phenylethylmalonylurea, D-myb, other neoplasm, metal ion regulated sequence-specific DNA binding, n[fah], metal ion regulated proximal promoter sequence-specific DNA 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promoter sequence-specific DNA binding, DMyb, M16449, trp63, NICD, Squamous Epithelial Cell, relational structural quality, CT13012, Glandular Epithelial Cell, dmyb, Cancer, Transitional, 16-178, tp73l, 16-55, Squamous Cells, Malignant Neoplasm, protein complex, scalp defect congenital, Proteins, Keratinocyte transcription factor KET, zinc ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, homeobox 1, Factor, anon-EST:Liang-1.12, Cell, transcription factor activity, development, 1-Aminocyclopropane-1-carboxylic acid, prophase chromosome, MT, Adenocystic Carcinoma, Phenobarbituric Acid, native protein, Lineage, Cuboidal Glandular Epithelial Cells, Gardenal, TACC, Cystic Carcinoma, Protein, spl, Neoplasm, RNA polymerase II transcription factor activity, Cystic Carcinomas, Phenobarbital, CG8723, 1.1, Sodium, TP53L, nd, Columnar Glandular Epithelial Cells, p53CP, metal ion regulated core promoter proximal region sequence-specific DNA binding RNA polymerase II transcription factor activity, KNOTTED1-like homeobox gene 5, INSDC_feature:regulatory, Phenylaethylbarbitursaeure, slow speed, 5-ethyl-5-phenyl-, primary cancer, Luminal, frequent, distinct, DmelCG11198, np63, interphase chromosome, D-tacc, TP53CP, 5-Ethyl-5-phenylbarbituric acid, Lineages, postnatal growth, Glandular Epithelial Cells, Phenylethylbarbituric, Cancers, metal ion regulated core promoter proximal region sequence-specific binding, copper ion regulated core promoter proximal region sequence-specific binding, ACAC, malignant tumor, TACCdm, D-TACC, F10N7.150, Protein Gene Products, Gene Proteins, efg, cribriform carcinoma, Tcp-1, ACC1, Adenoid Cystic Carcinoma, Cylindroma, CCT, CG3936, growth, Neoplasia, Xp63, PhenobarbitonefalseDAC for ACC StudyData Access Committee EGAC00001000376EGAC00001000376960626829750EGAS00001001457EGAD00001001662