Abstract
NSD1 mutations are recurrent in pediatric ALL and induce a distinct chromatin signature.
Major finding: NSD1 mutations are recurrent in pediatric ALL and induce a distinct chromatin signature.
Approach: Quantitative mass spectrometry was used to measure bulk histone modification levels across cell lines.
Impact: Chromatin profiling can reveal the epigenetic consequences of genetic or chemical perturbations.
The epigenomes of cancer cells are commonly altered, but efforts to comprehensively study epigenetic changes in cancer cells have been hindered by the limited availability of antibodies capable of recognizing specific histone modifications. Jaffe and colleagues devised a mass spectrometry–based method to simultaneously quantify levels of multiple histone modifications in bulk chromatin and used this technique to profile 42 distinct histone H3 modifications in a subset of hematologic cancer cell lines in the Cancer Cell Line Encyclopedia (CCLE). Unsupervised clustering grouped the data into six chromatin states, with one distinguished by increased H3 lysine 36 dimethylation (H3K36me2) and lower levels of unmodified H3K36. Six of the thirteen cell lines in this cluster harbored a t(4;14) translocation that leads to the overexpression of the H3K36 methyltransferase nuclear receptor SET domain-containing 2 (NSD2; also known as MMSET). However, the remaining cell lines did not have a t(4;14) translocation, prompting an analysis of the genomic features of these cell lines. Remarkably, each one harbored an NSD2 coding variant that resulted in an E1099K substitution in the NSD2 SET domain. The E1099K protein had increased methyltransferase activity in vitro, and its expression in an NSD2-deficient cell line increased H3K36me3 dimethylation in association with increased anchorage-independent growth. NSD2 mutations were enriched in pediatric acute lymphoblastic leukemia (ALL) cell lines in the CCLE, and growth and tumorigenicity of these cells were dependent on NSD2. Exon sequencing of NSD2 in a larger set of pediatric cancers identified NSD2 mutations in 7.5% of B-cell ALLs (B-ALL) overall and 20% of ETV6–RUNX1-positive B-ALL samples. These findings, which implicate NSD2-dependent H3K36 hypermethylation as a driving event in a subset of pediatric ALLs, highlight the potential of mass spectrometry chromatin profiling to rapidly uncover epigenetic consequences of cancer-associated mutations.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
RSS Feeds