RAG mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 Acute Lymphoblastic Leukemia (Whole_Genome_sequencing_data)

The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL), is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize the critical secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, accounting for at least 43% of genomic rearrangements and characterized by the presence of recombination signal sequence motifs near the breakpoints; incorporation of non-templated sequence at the junction and a ten-fold enrichment at promoters and enhancers of genes actively transcribed in early B-lineage development. Single-cell tracking shows that this mechanism is not restricted to one founder cell but is rather active throughout leukemic evolution. Integration of point mutation and rearrangement data identifies recurrent inactivation of ATF7IP and MGA as two new tumor suppressor genes.Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1 lymphoblasts, striking promoters and enhancers of the genes that normally control B-cell differentiation.

ETV6-RUNX1融合基因，存在于25%的儿童急性淋巴细胞白血病（ALL）病例中，虽在子宫内获得，但需额外的体细胞突变以形成明显的白血病。本研究利用外显子测序和低覆盖度全基因组测序技术，对白血病转化相关的关键二级事件进行了表征。RAG介导的删除突变成为主要的突变过程，占基因组重排事件的至少43%，其特征是断裂点附近存在重组信号序列模式；非模板序列在连接处的插入以及在早期B系发育过程中活跃转录的基因的启动子和增强子区域的十倍富集。单细胞追踪研究表明，这一机制并非局限于一个原始细胞，而是在整个白血病进化过程中持续活跃。整合点突变和重排数据识别出ATF7IP和MGA的反复失活，作为两个新的肿瘤抑制基因。因此，一个极为简约的突变过程改变了ETV6-RUNX1淋巴母细胞，影响正常调控B细胞分化的基因的启动子和增强子。