Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA.
Adv Exp Med Biol. 2021;1283:53-62. doi: 10.1007/978-981-15-8104-5_4.
Primary bone tumors are rare cancers that cause significant morbidity and mortality. The recent identification of recurrent mutations in histone genes H3F3A and H3F3B within specific bone cancers, namely, chondroblastomas and giant cell tumors of bone (GCTB), has provided insights into the cellular and molecular origins of these neoplasms and enhanced understanding of how histone variants control chromatin function. Somatic mutations in H3F3A and H3F3B produce oncohistones, H3.3G34W and H3.3K36M, in more than nine of ten GCTB and chondroblastomas, respectively. Incorporation of the mutant histones into nucleosomes inhibits histone methyltransferases NSD2 and SETD2 to alter the chromatin landscape and change gene expression patterns that control cell proliferation, survival, and differentiation, as well as DNA repair and chromosome stability. The discovery of these histone mutations has facilitated more accurate diagnoses of these diseases and stratification of malignant tumors from benign tumors so that appropriate care can be delivered. The broad-scale epigenomic and transcriptomic changes that arise from incorporation of mutant histones into chromatin provide opportunities to develop new and disease-specific therapies. In this chapter, we review how mutant histones inhibit SETD2 and NSD2 function in bone tumors and discuss how this information could lead to better treatments for these cancers.
原发性骨肿瘤是罕见的癌症，会导致严重的发病率和死亡率。最近在特定的骨癌（即软骨母细胞瘤和骨巨细胞瘤）中发现组蛋白基因 H3F3A 和 H3F3B 的反复突变，为这些肿瘤的细胞和分子起源提供了新的认识，并增强了对组蛋白变体如何控制染色质功能的理解。H3F3A 和 H3F3B 的体细胞突变分别在超过十分之九的 GCTB 和软骨母细胞瘤中产生癌组蛋白 H3.3G34W 和 H3.3K36M。突变组蛋白掺入核小体抑制组蛋白甲基转移酶 NSD2 和 SETD2，改变染色质景观并改变控制细胞增殖、存活和分化以及 DNA 修复和染色体稳定性的基因表达模式。这些组蛋白突变的发现促进了这些疾病的更准确诊断，并对良恶性肿瘤进行分层，以便提供适当的治疗。突变组蛋白掺入染色质引起的广泛表观基因组和转录组变化为开发新的、针对疾病的治疗方法提供了机会。在本章中，我们回顾了突变组蛋白如何抑制骨肿瘤中的 SETD2 和 NSD2 功能，并讨论了这些信息如何为这些癌症提供更好的治疗方法。
