Stegmeier, Frank, Jaffe, Jacob, Chan, Ho Man, Wang, Yan, Mcdonald Iii, Earl, Liu, Jun, Keen, Nicholas, Sellers, William, Livi, Garraway, Grigoriy, Kryukov, Hu, Min, Zhang, Jingui and Downing, James (2013) Global chromatin profiling reveals NSD2 mutation in pediastric acute lymphoblastic leukemia. Nature Genetics.

Abstract

Epigenetic dysregulation is an emerging new hallmark of cancers, and the identification of recurrent somatic mutations in chromatin modifying enzymes implies a causal role for altered chromatin states in tumorigenesis2,25. While the genomic characterization of cancers is well advanced29, our current understanding of cancer epigenomes is rather limited. In this study, we developed a robust, high-information content mass spectrometry approach to profile global histone modifications across 115 human cancer cell lines, which identified distinct patterns of molecular chromatin signatures (MCS). One MCS cluster displayed high H3K27 trimethylation and strongly correlated with EZH2 gain-of-function mutations. Another MCS cluster was characterized by increased H3K36 dimethylation that correlated with elevated NSD2 activity. This cluster revealed that acute lymphoblastic leukemia (ALL) cell lines carrying a novel mutation of NSD2 (E1099K) exhibit an MCS highly similar to that of cell lines harboring an activating NSD2 translocation. Using next-generation sequencing of a large collection of pediatric acute lymphoblastic leukemias (ALL), NSD2 E1099K mutations were identified in approximately 14% of ETV subtype ALLs. The NSD2 E1099K mutation is localized to the catalytic SET domain and leads to hyperactive histone methyltransferase activity. Disruption of NSD2 activity selectively inhibited the proliferation of cell lines harboring the NSD2 mutations, indicating dependence on the dysregulated epigenetic state. These findings identify NSD2 as a promising therapeutic target for pediatric ALL and provide a general framework towards systematic annotation of cancer epigenomes through MCS profiling.

Item Type:	Article
Keywords:	NSD2, epigenetics, histone profiling
Date Deposited:	13 Oct 2015 13:13
Last Modified:	13 Oct 2015 13:13
URI:	https://oak.novartis.com/id/eprint/9447