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

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, 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 › Article › peer-review

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
Pages (from-to)	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

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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10.1016/j.celrep.2023.112373

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Smits, W. K., Vermeulen, C., Hagelaar, R., Kimura, S., Vroegindeweij, E. M., Buijs-Gladdines, J. G. C. A. M., 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., & Meijerink, J. P. 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), 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.",

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",

author = "Smits, {Willem K} and Carlo Vermeulen and Rico Hagelaar and Shunsuke Kimura and Vroegindeweij, {Eric M} and Buijs-Gladdines, {Jessica G C A M} 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 Meijerink, {Jules P P}",

year = "2023",

month = apr,

day = "25",

doi = "10.1016/j.celrep.2023.112373",

language = "English",

volume = "42",

pages = "112373",

journal = "Cell reports",

issn = "2211-1247",

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Smits, WK, Vermeulen, C, Hagelaar, R, Kimura, S, Vroegindeweij, EM, Buijs-Gladdines, JGCAM, 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 & Meijerink, JPP 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, pp. 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 - 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

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 - Humans

KW - CCCTC-Binding Factor/genetics

KW - Chromatin

KW - Enhancer Elements, Genetic/genetics

KW - Mutation

KW - Oncogenes

KW - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics

KW - Repressor Proteins/genetics

KW - Transcription Factors/metabolism

KW - Tumor Suppressor Proteins/metabolism

UR - https://www.mendeley.com/catalogue/03562587-930c-3e59-b4d5-a8c8eb90e480/

U2 - 10.1016/j.celrep.2023.112373

DO - 10.1016/j.celrep.2023.112373

M3 - Article

C2 - 37060567

SN - 2211-1247

VL - 42

SP - 112373

JO - Cell reports

JF - Cell reports

IS - 4

ER -

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

Abstract

Keywords

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