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; prinses maxima; 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; prinses maxima

doi:10.1016/j.celrep.2023.112373

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, prinses maxima, 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, prinses maxima^*

^*Corresponding author for this work

Cell biology

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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 language	English
Article number	112373
Journal	Cell Reports
Volume	42
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2023.112373
Publication status	Published - 25 Apr 2023

Bibliographical note

ACKNOWLEDGMENTS:
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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Cite this

Smits, W. K., Vermeulen, C., Hagelaar, R., Kimura, S., Vroegindeweij, E. M., maxima, P., van de Geer, E., Verstegen, M. J. A. M., Splinter, E., van Reijmersdal, S. V., Buijs, A., Galjart, N., van Eyndhoven, W., van Min, M., Kuiper, R., Kemmeren, P., Mullighan, C. G., de Laat, W., & maxima, P. (2023). Elevated enhancer-oncogene contacts and higher oncogene expression levels by recurrent CTCF inactivating mutations in acute T cell leukemia. Cell Reports, 42(4), Article 112373. https://doi.org/10.1016/j.celrep.2023.112373

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title = "Elevated enhancer-oncogene contacts and higher oncogene expression levels by recurrent CTCF inactivating mutations in acute T cell leukemia",

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.",

author = "Smits, {Willem K.} and Carlo Vermeulen and Rico Hagelaar and Shunsuke Kimura and Vroegindeweij, {Eric M.} and prinses maxima and {van de Geer}, Ellen and Verstegen, {Marjon J.A.M.} and Erik Splinter and {van Reijmersdal}, {Simon V.} and Arjan Buijs and Niels Galjart and {van Eyndhoven}, Winfried and {van Min}, Max and Roland Kuiper and Patrick Kemmeren and Mullighan, {Charles G.} and {de Laat}, Wouter and prinses maxima",

note = "ACKNOWLEDGMENTS: 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: {\textcopyright} 2023 The Authors",

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Smits, WK, Vermeulen, C, Hagelaar, R, Kimura, S, Vroegindeweij, EM, maxima, P, van de Geer, E, Verstegen, MJAM, Splinter, E, van Reijmersdal, SV, Buijs, A, Galjart, N, van Eyndhoven, W, van Min, M, Kuiper, R, Kemmeren, P, Mullighan, CG, de Laat, W & maxima, P 2023, 'Elevated enhancer-oncogene contacts and higher oncogene expression levels by recurrent CTCF inactivating mutations in acute T cell leukemia', Cell Reports, vol. 42, no. 4, 112373. https://doi.org/10.1016/j.celrep.2023.112373

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 - maxima, prinses

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 - maxima, prinses

N1 - ACKNOWLEDGMENTS: 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.

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U2 - 10.1016/j.celrep.2023.112373

DO - 10.1016/j.celrep.2023.112373

M3 - Article

C2 - 37060567

AN - SCOPUS:85152703129

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 4

M1 - 112373

ER -

Elevated enhancer-oncogene contacts and higher oncogene expression levels by recurrent CTCF inactivating mutations in acute T cell leukemia

Abstract

Bibliographical note

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