Detection of Enhancer-Associated Rearrangements Reveals Mechanisms of Oncogene Dysregulation in B-cell Lymphoma.
Detection of Enhancer-Associated Rearrangements Reveals Mechanisms of Oncogene Dysregulation in B-cell Lymphoma.
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DOI：
10.1158/2159-8290.cd-15-0370
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发表时间：
2015-10
期刊：
影响因子：
28.2
通讯作者：
Bernstein BE
中科院分区：
文献类型：
--
作者：
Ryan RJ;Drier Y;Whitton H;Cotton MJ;Kaur J;Issner R;Gillespie S;Epstein CB;Nardi V;Sohani AR;Hochberg EP;Bernstein BE
B细胞淋巴瘤经常包含基因组重排，导致癌基因激活的异源远端调控元件。我们利用了一种新的方法，称为“通过染色质免疫沉淀精确定位增强子相关重排”或PEAR-ChIP，同时映射增强子活性和淋巴瘤细胞系和患者活检组织中的近端重排。该方法检测涉及已知癌症基因的重排，包括CCND 1、BCL 2、MYC、PDCD 1 LG 2、NOTCH 1、CIITA和SGK 1，以及可能具有致癌意义的新型增强子复制事件。我们确定了MYC基因座中淋巴瘤亚型特异性增强子，这些增强子在MYC激活重排的淋巴瘤中沉默，并与改变淋巴瘤风险的生殖系多态性相关。我们表明，BCL 6基因座增强子被BCL 6激活转录因子MEF 2B乙酰化，并可以进行基因组复制，或靶向MYC启动子激活的背景下，“假双重打击”t（3;8）（q27;q24）重排连接BCL 6和MYC基因座。我们的工作提供了关于增强子驱动的癌基因激活淋巴瘤的新见解。
B-cell lymphomas frequently contain genomic rearrangements that lead to oncogene activation by heterologous distal regulatory elements. We utilized a novel approach, termed ‘Pinpointing Enhancer-Associated Rearrangements by Chromatin Immunoprecipitation’ or PEAR-ChIP, to simultaneously map enhancer activity and proximal rearrangements in lymphoma cell lines and patient biopsies. This method detects rearrangements involving known cancer genes, including CCND1, BCL2, MYC, PDCD1LG2, NOTCH1, CIITA, and SGK1, as well as novel enhancer duplication events of likely oncogenic significance. We identify lymphoma subtype-specific enhancers in the MYC locus that are silenced in lymphomas with MYC-activating rearrangements and are associated with germline polymorphisms that alter lymphoma risk. We show that BCL6-locus enhancers are acetylated by the BCL6-activating transcription factor MEF2B, and can undergo genomic duplication, or target the MYC promoter for activation in the context of a “pseudo-double-hit” t(3;8)(q27;q24) rearrangement linking the BCL6 and MYC loci. Our work provides novel insights regarding enhancer-driven oncogene activation in lymphoma.