Clarifying the Impact of Polycomb Complex Component Disruption in Human Cancers
Clarifying the Impact of Polycomb Complex Component Disruption in Human Cancers
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DOI：
10.1158/1541-7786.mcr-13-0596
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发表时间：
2014-02
影响因子：
5.2
通讯作者：
Yukiya Yamamoto;A. Abe;N. Emi
中科院分区：
文献类型：
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作者：
Yukiya Yamamoto;A. Abe;N. Emi
正常转录控制的失调是发育性疾病和癌症的主要原因。在高等真核生物中，多梳蛋白形成染色质修饰复合物，在转录上沉默基因组区域。BCL6协同抑制因子（bcl）复合体包括无名指蛋白1B （RNF2/RING1B）、多梳组无名指1 （PCGF1）和赖氨酸特异性去甲基化酶2B (KDM2B)，并且在非甲基化的CpG岛上被独特地吸收，在那里它去除组蛋白H3K36me2并诱导抑制组蛋白H2A单泛素化。生殖系BCOR突变已在眼面心性和Lenz小眼综合征患者中检测到，这是一种遗传性疾病。最近，BCOR和BCOR样1 （BCORL1）嵌合融合转录物的几种变体被报道在人类癌症中，包括急性早幼粒细胞白血病、骨肉瘤和肝细胞癌。此外，大规模平行测序已经在急性髓性白血病（AML）、骨髓增生异常综合征（MDS）、慢性髓单核细胞白血病、髓母细胞瘤和视网膜母细胞瘤患者中发现了失活的体细胞BCOR和BCORL1突变。更重要的是，伴有BCOR突变的AML和MDS患者预后较差。这一观点强调了BCOR突变的检测以及BCOR和BCORL1的融合转录本，并讨论了它们对诊断癌症亚型和估计患者治疗反应的重要性。此外，这一观点提出需要额外的功能研究来阐明BCOR和BCORL1在癌症中被破坏的致癌机制，以及这可能如何导致新疗法的发展。Mol - Cancer Res；12 (4);479 - 84。AACR©2014。
The dysregulation of proper transcriptional control is a major cause of developmental diseases and cancers. Polycomb proteins form chromatin-modifying complexes that transcriptionally silence genome regions in higher eukaryotes. The BCL6 corepressor (BCOR) complex comprises ring finger protein 1B (RNF2/RING1B), polycomb group ring finger 1 (PCGF1), and lysine-specific demethylase 2B (KDM2B) and is uniquely recruited to nonmethylated CpG islands, where it removes histone H3K36me2 and induces repressive histone H2A monoubiquitylation. Germline BCOR mutations have been detected in patients with oculofaciocardiodental and Lenz microphthalmia syndromes, which are inherited conditions. Recently, several variants of BCOR and BCOR-like 1 (BCORL1) chimeric fusion transcripts were reported in human cancers, including acute promyelocytic leukemia, bone sarcoma, and hepatocellular carcinoma. In addition, massively parallel sequencing has identified inactivating somatic BCOR and BCORL1 mutations in patients with acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myelomonocytic leukemia, medulloblastoma, and retinoblastoma. More importantly, patients with AML and MDS with BCOR mutations exhibit poor prognosis. This perspective highlights the detection of BCOR mutations and fusion transcripts of BCOR and BCORL1 and discusses their importance for diagnosing cancer subtypes and estimating the treatment responses of patients. Furthermore, this perspective proposes the need for additional functional studies to clarify the oncogenic mechanism by which BCOR and BCORL1 are disrupted in cancers, and how this may lead to the development of novel therapeutics. Mol Cancer Res; 12(4); 479–84. ©2014 AACR.