Elevated enhancer-oncogene contacts and higher oncogene expression levels by recurrent CTCF inactivating mutations in acute T cell leukemia
Willem K. Smits,
Carlo Vermeulen,
Rico Hagelaar,
Shunsuke Kimura,
Eric M. Vroegindeweij,
Jessica G.C.A.M. Buijs-Gladdines,
Ellen van de Geer,
Marjon J.A.M. Verstegen,
Erik Splinter,
Simon V. van Reijmersdal,
Arjan Buijs,
Niels Galjart,
Winfried van Eyndhoven,
Max van Min,
Roland Kuiper,
Patrick Kemmeren,
Charles G. Mullighan,
Wouter de Laat,
Jules P.P. Meijerink
Affiliations
Willem K. Smits
Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
Carlo Vermeulen
Oncode Institute, Utrecht, the Netherlands; Hubrecht Institute-KNAW, Utrecht, the Netherlands; Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
Rico Hagelaar
Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Oncode Institute, Utrecht, the Netherlands
Shunsuke Kimura
Laboratory of Pathology, St. Jude’s Children’s Research Hospital, Memphis TN, USA
Eric M. Vroegindeweij
Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
Jessica G.C.A.M. Buijs-Gladdines
Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
Ellen van de Geer
Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
Marjon J.A.M. Verstegen
Oncode Institute, Utrecht, the Netherlands; Hubrecht Institute-KNAW, Utrecht, the Netherlands
Erik Splinter
Cergentis BV, Utrecht, the Netherlands
Simon V. van Reijmersdal
Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
Arjan Buijs
Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
Niels Galjart
Department of Cell Biology, Erasmus University Medical Center Rotterdam, Rotterdam, the Netherlands
Winfried van Eyndhoven
Diagnostics and Genomics Group, Agilent Technologies, Amstelveen, the Netherlands
Max van Min
Cergentis BV, Utrecht, the Netherlands
Roland Kuiper
Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
Patrick Kemmeren
Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
Charles G. Mullighan
Laboratory of Pathology, St. Jude’s Children’s Research Hospital, Memphis TN, USA
Wouter de Laat
Oncode Institute, Utrecht, the Netherlands; Hubrecht Institute-KNAW, Utrecht, the Netherlands
Jules P.P. Meijerink
Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands; Corresponding author
Summary: 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.
