Elevated enhancer-oncogene contacts and higher oncogene expression levels by recurrent CTCF inactivating 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 deregulated global gene expression. In patients with T cell acute lymphoblastic leukemia (T-ALL), we find that acquired monoallelic CTCF-inactivating events drive subtle and local genomic effects in nearly half of t(5; 14) (q35; q32.2) rearranged patients, especially when CTCF-binding 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 abrogates enhancer insulation by weakening competitive looping while favoring TLX3 promoter to BCL11B enhancer looping, which elevates oncogene expression levels and leukemia burden. [Display omitted] •Monoallelic CTCF aberrations are associated with patients with TLX3-BCL11B-rearranged T-ALL•CTCF aberrations coincide with intervening CTCF sites in BCL11B-TLX3 breakpoint regions•Intervening CTCF sites reduce oncogene levels by promoting alternative promoter loops•Aberrations that lower functional CTCF levels restore enhancer-promoter interactions Smits et al. report that TLX3 chromosomal translocations in T cell acute lymphoblastic leukemia patients recurrently include intervening CTCF-binding sites in the breakpoint area. Pressure to acquire inactivating aberrations in CTCF abrogate consequential enhancer insulation that promotes TLX3 promoter to BCL11B enhancer looping boosts higher oncogene expression levels and leukemia burden.