Gain-of-function mutation of chromatin regulators as a tumorigenic mechanism and an opportunity for therapeutic intervention.
Gain-of-function mutation of chromatin regulators as a tumorigenic mechanism and an opportunity for therapeutic intervention.
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染色质调节剂的功能性突变是一种肿瘤的机制和治疗干预的机会。
DOI：
10.1097/cco.0000000000000151
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发表时间：
2015-01
影响因子：
3.4
通讯作者：
Vakoc CR
中科院分区：
文献类型：
--
作者：
Shen C;Vakoc CR
正如激酶抑制剂在激酶突变型恶性肿瘤中的临床疗效所证明的那样，驱动癌症发病机制的体细胞功能获得突变是治疗干预的良好机会。在这里，我们讨论了最近发现的染色质调控机制中促进癌症发病机制的功能获得突变。本文将回顾目前对潜在分子机制和直接化学抑制的治疗潜力的理解。在B细胞肿瘤的不同亚群中发现了增加EZH2和NSD2组蛋白甲基转移酶催化活性的点突变，它们分别通过提高H3K27三甲基化或H3K36二甲基化的整体水平来促进细胞转化。此外，在某些儿童癌症中发现组蛋白H3突变，通过主要干扰组蛋白甲基转移酶活性导致H3K27和H3K36甲基化重编程。最后，涉及染色质调节基因的染色体易位可导致融合癌蛋白的形成，其作用机制是直接修饰染色质。虽然总体上相对罕见，但染色质调节因子的功能获得突变在遗传定义的癌症患者亚群中代表了引人注目的治疗靶点。然而，表观遗传学治疗在肿瘤学中更广泛的临床影响将需要增加对非突变染色质调节因子如何作为癌症特异性依赖的理解。
Somatic gain-of-function mutations that drive cancer pathogenesis are well-established opportunities for therapeutic intervention, as demonstrated by the clinical efficacy of kinase inhibitors in kinase-mutant malignancies. Here, we discuss recently discovered gain-of-function mutations in chromatin regulatory machineries that promote the pathogenesis of cancer. The current understanding of underlying molecular mechanisms and the therapeutic potential for direct chemical inhibition will be reviewed. Point mutations that increase the catalytic activity of EZH2 and NSD2 histone methyltransferases are found in distinct subsets of B cell neoplasms, which promote cell transformation by elevating the global level of H3K27 tri-methylation or H3K36 di-methylation, respectively. In addition, mutations in histone H3 have been identified in certain pediatric cancers which cause reprogramming of H3K27 and H3K36 methylation by dominantly interfering with histone methyltransferase activity. Finally, chromosomal translocations involving chromatin regulator genes can lead to the formation of fusion oncoproteins that directly modify chromatin as their mechanism of action. While relatively rare in aggregate, gain-of-function mutations in chromatin regulators represent compelling therapeutic targets in genetically-defined subsets of cancer patients. However, a broader clinical impact for epigenetic therapies in oncology will require an increased understanding of how non-mutated chromatin regulators function as cancer-specific dependencies.