title: Differentiation of NUT midline carcinoma by epigenomic reprogramming.
abstract: NUT midline carcinoma (NMC) is a lethal pediatric tumor defined by the presence of BRD-NUT fusion proteins that arrest differentiation. Here we explore the mechanisms underlying the ability of BRD4-NUT to prevent squamous differentiation. In both gain-of and loss-of-expression assays, we find that expression of BRD4-NUT is associated with globally decreased histone acetylation and transcriptional repression. Bulk chromatin acetylation can be restored by treatment of NMC cells with histone deacetylase inhibitors (HDACi), engaging a program of squamous differentiation and arrested growth in vitro that closely mimics the effects of siRNA-mediated attenuation of BRD4-NUT expression. The potential therapeutic utility of HDACi differentiation therapy was established in three different NMC xenograft models, where it produced significant growth inhibition and a survival benefit. Based on these results and translational studies performed with patient-derived primary tumor cells, a child with NMC was treated with the FDA-approved HDAC inhibitor, vorinostat. An objective response was obtained after five weeks of therapy, as determined by positron emission tomography. These findings provide preclinical support for trials of HDACi in patients with NMC.
authors: Department of Pathology, Division of Women's and Perinatal Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors: Brian E
authors: BE
authors: Schwartz
authors: Matthias D
authors: MD
authors: Hofer
authors: Madeleine E
authors: ME
authors: Lemieux
authors: Daniel E
authors: DE
authors: Bauer
authors: Michael J
authors: MJ
authors: Cameron
authors: Nathan H
authors: NH
authors: West
authors: Elin S
authors: ES
authors: Agoston
authors: Nicolas
authors: N
authors: Reynoird
authors: Saadi
authors: S
authors: Khochbin
authors: Tan A
authors: TA
authors: Ince
authors: Amanda
authors: A
authors: Christie
authors: Katherine A
authors: KA
authors: Janeway
authors: Sara O
authors: SO
authors: Vargas
authors: Antonio R
authors: AR
authors: Perez-Atayde
authors: Jon C
authors: JC
authors: Aster
authors: Stephen E
authors: SE
authors: Sallan
authors: Andrew L
authors: AL
authors: Kung
authors: James E
authors: JE
authors: Bradner
authors: Christopher A
authors: CA
authors: French
mesh_terms: D000107:Acetylation; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics*; D002648:Child; D005260:Female; D055785:Gene Knockdown Techniques; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008479:Mediastinal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009303:Nasopharyngeal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection; D014183:Transplantation, Heterologous; D000077337:Vorinostat
chemical_list: C471990:BRD4-NUT fusion oncogene protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C000630260:NUTM1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D034741:RNA, Small Interfering; D000077337:Vorinostat