Abstract 2930: Global chromatin profiling reveals NSD2 mutation in pediatric ALL

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Epigenetic dysregulation is an emerging hallmark of cancers. We developed a high-information-content mass spectrometry approach to profile global histone modifications in human cancers. When applied to 115 lines of the Cancer Cell Line Encyclopedia1, this approach identified distinct molecular chromatin signatures. One signature was characterized by increased H3K36 dimethylation, exhibited by several lines harboring NSD2 translocations. A novel NSD2 p.E1099K variant was identified in non-translocated acute lymphoblastic leukemia (ALL) lines sharing this signature. Ectopic expression of the variant induced a chromatin signature characteristic of NSD2 hyperactivation and promoted transformation. NSD2 knockdown selectively inhibited the proliferation of NSD2-mutant lines and impaired the in vivo growth of an NSD2-mutant ALL xenograft. Sequencing analysis of >1000 pediatric cancer genomes identified the NSD2 p.E1099K mutation in 14% of t(12;21)[ETV6-RUNX1]-containing ALLs. These findings identify NSD2 as a potential therapeutic target for pediatric ALL and provide a general framework for the functional annotation of cancer epigenomes. 1. Barretina,J. et al. The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483, 603-607 (2012). Citation Format: Ho Man Chan, Jacob D. Jaffe, Yan Wang, Jinghui Zhang, Robert Huether, Gregory V. Kryukov, Hyo-eun C. Bhang, Jordan E. Taylor, Min Hu, Nathan P. Englund, Feng Yan, Zhaofu Wang, E Robert McDonald III, Lei Wei, Jing Ma, John Easton, Zhengtian Yu, Rosalie deBeaumount, Veronica Gibaja, Kavitha Venkatesan, Robert Schlegel, William R. Sellers, Nicholas Keen, Jun Liu, Giordano Caponigro, Jordi Barretina, Vesselina G. Cooke, Charles Mullighan, Steven A. Carr, James R. Downing, Levi A. Garraway, Frank Stegmeier. Global chromatin profiling reveals NSD2 mutation in pediatric ALL. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2930. doi:10.1158/1538-7445.AM2014-2930