I will first present an integrative framework for comprehensively identifying structural variation and investigating their effect on 3D genome structure. For the first time, we applied next-generation optical mapping (BioNano Irys), high-throughput chromosome conformation capture (Hi-C) techniques, and whole genome sequencing to detect SVs in up to 35 commonly used normal and cancer cells. We further studied the impact of SVs on gene expression and high-order genome organization, such as the formation of novel topological associating domains (TADs) and enhancer hijacking events, and eventually on tumorigenesis. In the second project, I will introduce our recent effort on identifying causal variants in childhood acute lymphoblastic leukemia (ALL). Starting from targeted re-sequencing in more than 5,000 patients, we used a combination of high throughput genomics approach and genome editing with CRISPR/Cas9, and identified a regulatory variant that controls the transcription of a well-known onco-gene in ph-like ALL.