TY - JOUR
T1 - Elevated enhancer-oncogene contacts and higher oncogene expression levels by recurrent CTCF inactivating mutations in acute T cell leukemia
AU - Smits, Willem K
AU - Vermeulen, Carlo
AU - Hagelaar, Rico
AU - Kimura, Shunsuke
AU - Vroegindeweij, Eric M
AU - Buijs-Gladdines, Jessica G C A M
AU - van de Geer, Ellen
AU - Verstegen, Marjon J A M
AU - Splinter, Erik
AU - van Reijmersdal, Simon V
AU - Buijs, Arjan
AU - Galjart, Niels
AU - van Eyndhoven, Winfried
AU - van Min, Max
AU - Kuiper, Roland
AU - Kemmeren, Patrick
AU - Mullighan, Charles G
AU - de Laat, Wouter
AU - Meijerink, Jules P P
N1 - 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
PY - 2023/4/25
Y1 - 2023/4/25
N2 - 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.
AB - 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.
KW - BCL11B
KW - competitive chromatin looping
KW - CP: Cancer
KW - CTCF mutation
KW - enhancer insulation
KW - oncogene regulation
KW - T cell acute lymphoblastic leukemia
KW - TLX3
UR - http://www.scopus.com/inward/record.url?scp=85152703129&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2023.112373
DO - 10.1016/j.celrep.2023.112373
M3 - Article
C2 - 37060567
SN - 2211-1247
VL - 42
JO - Cell Reports
JF - Cell Reports
IS - 4
M1 - 112373
ER -