Elevated enhancer - oncogene contacts and higher oncogene expression levels by recurrent CTCF in activating mutations in acute T cell leukemia
Monoallelic inactivation of CCCTC-binding factor (CTCF) in human cancer drives altered methylated genomic states, altered CTCF occupancy at promoter and enhancer regions and deregulate global gene expression. In T-ALL patients, we found that acquired monoallelic CTCF-inactivating events drive subtle and local genomic effects in nearly half of t(5;14)(q35;q32.2) rearranged patients, and especially when CTCF bindings sites are preserved in between the BCL11B-enhancer and the TLX3 oncogene. These solitary intervening sites insulate TLX3 from the enhancer by inducing competitive looping to multiple binding sites near the TLX3 promoter. Reduced CTCF levels, or deletion of the intervening CTCF site weakens competitive looping while favors TLX3-promoter to BCL11B-enhancer looping that elevates oncogene expression levels and leukemia burden. Collectively, we reveal that lower CTCF levels abrogate enhancer insulation, allowing oncogene expression that drives leukemia development.