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

Research output: Contribution to journal/periodicalArticleScientificpeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)112373
JournalCell Reports
Volume42
Issue number4
DOIs
Publication statusPublished - 25 Apr 2023

Keywords

  • Humans
  • CCCTC-Binding Factor/genetics
  • Chromatin
  • Enhancer Elements, Genetic/genetics
  • Mutation
  • Oncogenes
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics
  • Repressor Proteins/genetics
  • Transcription Factors/metabolism
  • Tumor Suppressor Proteins/metabolism

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