Elevated Enhancer-Oncogene Contacts and Higher Oncogene Expression Levels by Recurrent CTCF Inactivating Mutations in Acute T Cell Leukemia
2021
Inactivating mutations in the CCCTC-binding factor (CTCF) in human cancer drive altered methylated genomic states, altered CTCF occupancy at promotor and enhancer regions and deregulate global gene expression. In T-ALL patients, we found that acquired inactivating CTCF 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. Loss of CTCF, 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 loss of CTCF abrogates enhancer insulation, allowing oncogene expression that drives leukemia development.
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