TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets

Bieke Decaesteker; Geertrui Denecker; Christophe van Neste; Emmy M. Dolman; Wouter van Loocke; Moritz Gartlgruber; Carolina Nunes; Fanny de Vloed; Pauline Depuydt; Karen Verboom; Dries Rombaut; Siebe Loontiens; Jolien de Wyn; Waleed M. Kholosy; Bianca Koopmans; Anke H. W. Essing; Carl Herrmann; Daniel Dreidax; Kaat Durinck; Dieter Deforce; Filip van Nieuwerburgh; Anton Henssen; Rogier Versteeg; Valentina Boeva; Gudrun Schleiermacher; Johan van Nes; Pieter Mestdagh; Suzanne Vanhauwaert; Johannes H. Schulte; Frank Westermann; Jan J. Molenaar; Katleen de Preter; Frank Speleman

doi:https://doi.org/10.1038/s41467-018-06699-9

TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets

Bieke Decaesteker, Geertrui Denecker, Christophe van Neste, Emmy M. Dolman, Wouter van Loocke, Moritz Gartlgruber, Carolina Nunes, Fanny de Vloed, Pauline Depuydt, Karen Verboom, Dries Rombaut, Siebe Loontiens, Jolien de Wyn, Waleed M. Kholosy, Bianca Koopmans, Anke H. W. Essing, Carl Herrmann, Daniel Dreidax, Kaat Durinck, Dieter DeforceFilip van Nieuwerburgh, Anton Henssen, Rogier Versteeg, Valentina Boeva, Gudrun Schleiermacher, Johan van Nes, Pieter Mestdagh, Suzanne Vanhauwaert, Johannes H. Schulte, Frank Westermann, Jan J. Molenaar, Katleen de Preter, Frank Speleman

Research output: Contribution to journal › Article › Academic › peer-review

62 Citations (Scopus)

Abstract

Chromosome 17q gains are almost invariably present in high-risk neuroblastoma cases. Here, we perform an integrative epigenomics search for dosage-sensitive transcription factors on 17q marked by H3K27ac defined super-enhancers and identify TBX2 as top candidate gene. We show that TBX2 is a constituent of the recently established core regulatory circuitry in neuroblastoma with features of a cell identity transcription factor, driving proliferation through activation of p21-DREAM repressed FOXM1 target genes. Combined MYCN/TBX2 knockdown enforces cell growth arrest suggesting that TBX2 enhances MYCN sustained activation of FOXM1 targets. Targeting transcriptional addiction by combined CDK7 and BET bromodomain inhibition shows synergistic effects on cell viability with strong repressive effects on CRC gene expression and p53 pathway response as well as several genes implicated in transcriptional regulation. In conclusion, we provide insight into the role of the TBX2 CRC gene in transcriptional dependency of neuroblastoma cells warranting clinical trials using BET and CDK7 inhibitors.

Original language	English
Pages (from-to)	4866
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06699-9
Publication status	Published - 2018

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Decaesteker, B., Denecker, G., van Neste, C., Dolman, E. M., van Loocke, W., Gartlgruber, M., Nunes, C., de Vloed, F., Depuydt, P., Verboom, K., Rombaut, D., Loontiens, S., de Wyn, J., Kholosy, W. M., Koopmans, B., Essing, A. H. W., Herrmann, C., Dreidax, D., Durinck, K., ... Speleman, F. (2018). TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets. Nature communications, 9(1), 4866. https://doi.org/10.1038/s41467-018-06699-9

@article{456909e5dd7b44a0b22f269976ab93ad,

title = "TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets",

abstract = "Chromosome 17q gains are almost invariably present in high-risk neuroblastoma cases. Here, we perform an integrative epigenomics search for dosage-sensitive transcription factors on 17q marked by H3K27ac defined super-enhancers and identify TBX2 as top candidate gene. We show that TBX2 is a constituent of the recently established core regulatory circuitry in neuroblastoma with features of a cell identity transcription factor, driving proliferation through activation of p21-DREAM repressed FOXM1 target genes. Combined MYCN/TBX2 knockdown enforces cell growth arrest suggesting that TBX2 enhances MYCN sustained activation of FOXM1 targets. Targeting transcriptional addiction by combined CDK7 and BET bromodomain inhibition shows synergistic effects on cell viability with strong repressive effects on CRC gene expression and p53 pathway response as well as several genes implicated in transcriptional regulation. In conclusion, we provide insight into the role of the TBX2 CRC gene in transcriptional dependency of neuroblastoma cells warranting clinical trials using BET and CDK7 inhibitors.",

author = "Bieke Decaesteker and Geertrui Denecker and {van Neste}, Christophe and Dolman, {Emmy M.} and {van Loocke}, Wouter and Moritz Gartlgruber and Carolina Nunes and {de Vloed}, Fanny and Pauline Depuydt and Karen Verboom and Dries Rombaut and Siebe Loontiens and {de Wyn}, Jolien and Kholosy, {Waleed M.} and Bianca Koopmans and Essing, {Anke H. W.} and Carl Herrmann and Daniel Dreidax and Kaat Durinck and Dieter Deforce and {van Nieuwerburgh}, Filip and Anton Henssen and Rogier Versteeg and Valentina Boeva and Gudrun Schleiermacher and {van Nes}, Johan and Pieter Mestdagh and Suzanne Vanhauwaert and Schulte, {Johannes H.} and Frank Westermann and Molenaar, {Jan J.} and {de Preter}, Katleen and Frank Speleman",

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doi = "https://doi.org/10.1038/s41467-018-06699-9",

language = "English",

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pages = "4866",

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Decaesteker, B, Denecker, G, van Neste, C, Dolman, EM, van Loocke, W, Gartlgruber, M, Nunes, C, de Vloed, F, Depuydt, P, Verboom, K, Rombaut, D, Loontiens, S, de Wyn, J, Kholosy, WM, Koopmans, B, Essing, AHW, Herrmann, C, Dreidax, D, Durinck, K, Deforce, D, van Nieuwerburgh, F, Henssen, A, Versteeg, R, Boeva, V, Schleiermacher, G, van Nes, J, Mestdagh, P, Vanhauwaert, S, Schulte, JH, Westermann, F, Molenaar, JJ, de Preter, K & Speleman, F 2018, 'TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets', Nature communications, vol. 9, no. 1, pp. 4866. https://doi.org/10.1038/s41467-018-06699-9

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T1 - TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets

AU - Decaesteker, Bieke

AU - Denecker, Geertrui

AU - van Neste, Christophe

AU - Dolman, Emmy M.

AU - van Loocke, Wouter

AU - Gartlgruber, Moritz

AU - Nunes, Carolina

AU - de Vloed, Fanny

AU - Depuydt, Pauline

AU - Verboom, Karen

AU - Rombaut, Dries

AU - Loontiens, Siebe

AU - de Wyn, Jolien

AU - Kholosy, Waleed M.

AU - Koopmans, Bianca

AU - Essing, Anke H. W.

AU - Herrmann, Carl

AU - Dreidax, Daniel

AU - Durinck, Kaat

AU - Deforce, Dieter

AU - van Nieuwerburgh, Filip

AU - Henssen, Anton

AU - Versteeg, Rogier

AU - Boeva, Valentina

AU - Schleiermacher, Gudrun

AU - van Nes, Johan

AU - Mestdagh, Pieter

AU - Vanhauwaert, Suzanne

AU - Schulte, Johannes H.

AU - Westermann, Frank

AU - Molenaar, Jan J.

AU - de Preter, Katleen

AU - Speleman, Frank

PY - 2018

Y1 - 2018

N2 - Chromosome 17q gains are almost invariably present in high-risk neuroblastoma cases. Here, we perform an integrative epigenomics search for dosage-sensitive transcription factors on 17q marked by H3K27ac defined super-enhancers and identify TBX2 as top candidate gene. We show that TBX2 is a constituent of the recently established core regulatory circuitry in neuroblastoma with features of a cell identity transcription factor, driving proliferation through activation of p21-DREAM repressed FOXM1 target genes. Combined MYCN/TBX2 knockdown enforces cell growth arrest suggesting that TBX2 enhances MYCN sustained activation of FOXM1 targets. Targeting transcriptional addiction by combined CDK7 and BET bromodomain inhibition shows synergistic effects on cell viability with strong repressive effects on CRC gene expression and p53 pathway response as well as several genes implicated in transcriptional regulation. In conclusion, we provide insight into the role of the TBX2 CRC gene in transcriptional dependency of neuroblastoma cells warranting clinical trials using BET and CDK7 inhibitors.

AB - Chromosome 17q gains are almost invariably present in high-risk neuroblastoma cases. Here, we perform an integrative epigenomics search for dosage-sensitive transcription factors on 17q marked by H3K27ac defined super-enhancers and identify TBX2 as top candidate gene. We show that TBX2 is a constituent of the recently established core regulatory circuitry in neuroblastoma with features of a cell identity transcription factor, driving proliferation through activation of p21-DREAM repressed FOXM1 target genes. Combined MYCN/TBX2 knockdown enforces cell growth arrest suggesting that TBX2 enhances MYCN sustained activation of FOXM1 targets. Targeting transcriptional addiction by combined CDK7 and BET bromodomain inhibition shows synergistic effects on cell viability with strong repressive effects on CRC gene expression and p53 pathway response as well as several genes implicated in transcriptional regulation. In conclusion, we provide insight into the role of the TBX2 CRC gene in transcriptional dependency of neuroblastoma cells warranting clinical trials using BET and CDK7 inhibitors.

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DO - https://doi.org/10.1038/s41467-018-06699-9

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SN - 2041-1723

VL - 9

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JO - Nature communications

JF - Nature communications

IS - 1

ER -

TBX2 is a neuroblastoma core regulatory circuitry component enhancing MYCN/FOXM1 reactivation of DREAM targets

Abstract

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