Elevated enhancer-oncogene contacts and higher oncogene expression levels by recurrent CTCF inactivating mutations in acute T cell leukemia
Smits, Willem K; Vermeulen, Carlo; Hagelaar, Rico; Kimura, Shunsuke; Vroegindeweij, Eric M; Buijs-Gladdines, Jessica G C A M; van de Geer, Ellen; Verstegen, Marjon J A M; Splinter, Erik; van Reijmersdal, Simon V; Buijs, Arjan; Galjart, Niels; van Eyndhoven, Winfried; van Min, Max; Kuiper, Roland; Kemmeren, Patrick; Mullighan, Charles G; de Laat, Wouter; Meijerink, Jules P P
(2023) Cell Reports, volume 42, issue 4
(Article)
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
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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.
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Keywords: BCL11B, competitive chromatin looping, CP: Cancer, CTCF mutation, enhancer insulation, oncogene regulation, T cell acute lymphoblastic leukemia, TLX3, General Biochemistry,Genetics and Molecular Biology, Journal Article
ISSN: 2211-1247
Publisher: Cell Press
Note: Funding Information: W.K.S., R.H., and E.M.V. were sponsored by the Dutch Cancer Society ( KWF-4691 ) and the “Kinderen Kankervrij” foundation (grants KiKa 2015-244 to E.M.V., KiKa 2013-219 to R.H., and KiKa 2017-295 to W.K.S.). E.v.d.G. was sponsored by KiKa core funding. W.K.S. and J.G.C.A.M.B.-G. are also sponsored by the foundation “ Stichting Kinder Oncologisch Centrum Rotterdam .” C.V. and M.J.A.M.V. were sponsored by the Foundation Leducq (grant 14CVD01 ). C.V. and M.J.A.M.V. were also sponsored by the Netherlands Scientific Organization NWO: NWO VICI-grant 724.012.003 , and C.V. is currently supported by a NWO Vidi Fellowship ( 639.072.715 ). C.G.M. is supported by the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital and a National Cancer Institute Outstanding Investigator Award R35 CA197695 . Publisher Copyright: © 2023 The Authors
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