Abstract PR01: Global chromatin profiling identifies NSD2 mutations in pediatric acute lymphoblastic leukemia

• Published in: Cancer research (Chicago, Ill.) Ill.), 2013-07, Vol.73 (13_Supplement), p.PR01-PR01
• Main Authors: Jaffe, Jacob, Wang, Yan, Chan, HoMan, Zhang, Jinghui, Huether, Roberts, Kryukov, Gregory, Taylor, Jordan, Hu, Min, Englund, Nathan, Yan, Feng, Wang, Zhaofu, Wei, Lei, Ma, Jing, Easton, John, Sellers, William R., Keen, Nicholas, Liu, Jun, Mullighan, Charles, Carr, Steven, Downing, James, Garraway, Levi, Stegmeier, Frank
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.CEC13-PR01

Epigenetic dysregulation is an emerging hallmark of cancers, and the identification of recurrent somatic mutations in chromatin modifying enzymes implies a causal role for altered chromatin states in tumorigenesis. While the genomic characterization of cancers is well advanced, our current understanding of cancer epigenomes is limited. Here, we developed a high-information-content mass spectrometry approach to profile global histone modifications in human cancer cells. When applied to 115 cell lines of the Cancer Cell Line Encyclopedia, this approach identified distinct molecular chromatin signatures (MCS) that provided novel insights into their epigenetic states. One MCS cluster, characterized by high H3K27 trimethylation, strongly correlated with EZH2 gain-of-function mutations, whereas another MCS cluster provided functional epigenetic correlates of EZH2 loss-of-function mutations. A third MCS cluster was characterized by increased H3K36 dimethylation and contained several cell lines harboring NSD2 translocations. Analysis of genomic correlates of the remaining cell lines within this third cluster identified a novel NSD2 E1099K variant in acute lymphoblastic leukemia (ALL) lines. Ectopic expression of the NSD2 E1099K variant induced a MCS profile characteristic of NSD2 hyperactivation and promoted transformation. Moreover, NSD2 knockdown selectively inhibited the proliferation of cell lines harboring NSD2 mutations. Massively parallel sequencing analysis of over 1000 pediatric cancer genomes identified the same NSD2 E1099K mutation in 14% of t(12;21)[ETV6-RUNX1]-containing ALLs. Together, these findings identify NSD2 as a potential therapeutic target for pediatric ALL and provide a general framework for the functional annotation of cancer epigenomes. Citation Format: Jacob Jaffe, Yan Wang, HoMan Chan, Jinghui Zhang, Roberts Huether, Gregory Kryukov, Jordan Taylor, Min Hu, Nathan Englund, Feng Yan, Zhaofu Wang, Lei Wei, Lei Wei, Jing Ma, John Easton, William R. Sellers, Nicholas Keen, Jun Liu, Jun Liu, Charles Mullighan, Steven Carr, James Downing, Levi Garraway, Frank Stegmeier. Global chromatin profiling identifies NSD2 mutations in pediatric acute lymphoblastic leukemia. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr PR01.