1] The Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. [2].
Nat Genet. 2013 Nov;45(11):1386-91. doi: 10.1038/ng.2777. Epub 2013 Sep 29.
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 from the Cancer Cell Line Encyclopedia, this approach identified distinct molecular chromatin signatures. One signature was characterized by increased histone 3 lysine 36 (H3K36) dimethylation, exhibited by several lines harboring translocations in NSD2, which encodes a methyltransferase. A previously unknown NSD2 p.Glu1099Lys (p.E1099K) variant was identified in nontranslocated acute lymphoblastic leukemia (ALL) cell 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 >1,000 pediatric cancer genomes identified the NSD2 p.E1099K alteration 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.
表观遗传失调是癌症的一个新兴标志。我们开发了一种高信息量的质谱分析方法，用于分析人类癌症中的全局组蛋白修饰。当应用于癌症细胞系百科全书（Cancer Cell Line Encyclopedia）中的 115 条系谱时，该方法确定了独特的分子染色质特征。其中一个特征是组蛋白 3 赖氨酸 36（H3K36）二甲基化增加，这在几个携带 NSD2 易位的系谱中表现出来，而 NSD2 编码一种甲基转移酶。在具有这种特征的非易位急性淋巴细胞白血病（ALL）细胞系中，鉴定出了先前未知的 NSD2 p.Glu1099Lys（p.E1099K）变体。该变体的异位表达诱导了与 NSD2 过度激活特征一致的染色质特征，并促进了转化。NSD2 敲低选择性地抑制了 NSD2 突变系的增殖，并损害了 NSD2 突变 ALL 异种移植物的体内生长。对 >1000 个儿科癌症基因组的测序分析在 14%的包含 t(12;21) ETV6-RUNX1 的 ALL 中鉴定出了 NSD2 p.E1099K 改变。这些发现确定了 NSD2 是儿科 ALL 的一个潜在治疗靶点，并为癌症表观基因组的功能注释提供了一个通用框架。
