Differentiation of NUT midline carcinoma by epigenomic reprogramming

Brian E. Schwartz, Matthias D. Hofer, Madeleine E. Lemieux, Daniel E. Bauer, Michael J. Cameron, Nathan H. West, Elin S. Agoston, Nicolas Reynoird, Saadi Khochbin, Tan A. Ince, Amanda Christie, Katherine A. Janeway, Sara O. Vargas, Antonio R. Perez-Atayde, Jon C. Aster, Stephen E. Sallan, Andrew L. Kung, James E. Bradner, Christopher A. French

Research output: Contribution to journalArticle

112 Scopus citations

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 patientderived 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.

Original languageEnglish (US)
Pages (from-to)2686-2696
Number of pages11
JournalCancer Research
Volume71
Issue number7
DOIs
StatePublished - Apr 1 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Schwartz, B. E., Hofer, M. D., Lemieux, M. E., Bauer, D. E., Cameron, M. J., West, N. H., Agoston, E. S., Reynoird, N., Khochbin, S., Ince, T. A., Christie, A., Janeway, K. A., Vargas, S. O., Perez-Atayde, A. R., Aster, J. C., Sallan, S. E., Kung, A. L., Bradner, J. E., & French, C. A. (2011). Differentiation of NUT midline carcinoma by epigenomic reprogramming. Cancer Research, 71(7), 2686-2696. https://doi.org/10.1158/0008-5472.CAN-10-3513