A mouse model of endemic Burkitt translocations reveals the long-range boundaries of Ig-mediated oncogene deregulation. Mus musculus

Igh/Myc translocations underlie both sporadic Burkitt lymphoma (BL) and the endemic clinical form affecting African children infected with malaria. However, while sporadic translocations decapitate Myc from 5' proximal regulatory elements, most endemic events occur hundreds of kilobases away from Myc. The origin of these rearrangements and how they deregulate oncogenes at such distances remain unclear. Here we recapitulate endemic BL-like translocations in plasmacytomas from uracil N-glycosylase (UNG) deficient mice. We demonstrate that in these animals, rare endemic-like translocations arise from non-targeted DNA breaks at Myc loci. Deep-sequencing analyses revealed that the deregulated 3' Igh enhancer alpha physically interacts with and remodels 0.45Mb of translocated chromatin. The results thus explain the long-range deregulation of oncogenes in human and mouse B cell tumors. Overall design: ChIP-Seq, 4C, and 1 RNASeq samples used to characterize mouse plasmacytoma cell lines and in vitro activated mouse B cells. Biological replicates are present for many of the samples.

免疫球蛋白重链（Igh）/Myc易位是散发性伯基特淋巴瘤（Burkitt lymphoma, BL）以及感染疟疾的非洲儿童所患地方性临床亚型伯基特淋巴瘤的致病基础。然而，散发性易位会将Myc基因与其5'近端调控元件分离，而多数地方性易位的断裂位点距离Myc基因可达数百千碱基对之遥。此类重排的起源以及它们如何在如此远距离下失调癌基因的机制至今仍未阐明。本研究在尿嘧啶N-糖苷酶（uracil N-glycosylase, UNG）缺陷小鼠的浆细胞瘤中重现了地方性BL样易位模型。我们证实，在该类小鼠中，罕见的地方性BL样易位起源于Myc基因位点的非靶向DNA断裂。深度测序分析显示，失调的3' Igh增强子α可与易位的0.45Mb染色质发生物理相互作用并对其进行染色质重塑。因此，本研究结果阐明了人类与小鼠B细胞肿瘤中癌基因的长距离失调机制。整体实验设计：本研究采用染色质免疫沉淀测序（ChIP-Seq）、环状染色质构象捕获（4C）以及RNA测序（RNA-Seq）样本，对小鼠浆细胞瘤细胞系与体外活化的小鼠B细胞进行表征。多数样本均设置了生物学重复。