ALK positively regulates MYCN activity through repression of HBP1 expression

Shana Claeys; Geertrui Denecker; Kaat Durinck; Bieke Decaesteker; Liselot M. Mus; Siebe Loontiens; Suzanne Vanhauwaert; Kristina Althoff; Caroline Wigerup; Daniel Bexell; Emmy Dolman; Kai Oliver Henrich; Lea Wehrmann; Ellen M. Westerhout; Jean Baptiste Demoulin; Candy Kumps; Tom Van Maerken; Genevieve Laureys; Christophe Van Neste; Bram De Wilde; Olivier De Wever; Frank Westermann; Rogier Versteeg; Jan J. Molenaar; Sven Påhlman; Johannes H. Schulte; Katleen De Preter; Frank Speleman

doi:10.1038/s41388-018-0595-3

ALK positively regulates MYCN activity through repression of HBP1 expression

Shana Claeys, Geertrui Denecker, Kaat Durinck, Bieke Decaesteker, Liselot M. Mus, Siebe Loontiens, Suzanne Vanhauwaert, Kristina Althoff, Caroline Wigerup, Daniel Bexell, Emmy Dolman, Kai Oliver Henrich, Lea Wehrmann, Ellen M. Westerhout, Jean Baptiste Demoulin, Candy Kumps, Tom Van Maerken, Genevieve Laureys, Christophe Van Neste, Bram De WildeOlivier De Wever, Frank Westermann, Rogier Versteeg, Jan J. Molenaar, Sven Påhlman, Johannes H. Schulte, Katleen De Preter, Frank Speleman

Group Molenaar

Onderzoeksoutput: Bijdrage aan tijdschrift › Artikel › peer review

22 Citaten (Scopus)

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ALK mutations occur in 10% of primary neuroblastomas and represent a major target for precision treatment. In combination with MYCN amplification, ALK mutations infer an ultra-high-risk phenotype resulting in very poor patient prognosis. To open up opportunities for future precision drugging, a deeper understanding of the molecular consequences of constitutive ALK signaling and its relationship to MYCN activity in this aggressive pediatric tumor entity will be essential. We show that mutant ALK downregulates the ‘HMG-box transcription factor 1’ (HBP1) through the PI ₃ K-AKT–FOXO3a signaling axis. HBP1 inhibits both the transcriptional activating and repressing activity of MYCN, the latter being mediated through PRC2 activity. HBP1 itself is under negative control of MYCN through miR-17~92. Combined targeting of HBP1 by PI ₃ K antagonists and MYCN signaling by BET- or HDAC-inhibitors blocks MYCN activity and significantly reduces tumor growth, suggesting a novel targeted therapy option for high-risk neuroblastoma.

Originele taal-2	Engels
Pagina's (van-tot)	2690-2705
Aantal pagina's	16
Tijdschrift	Oncogene
Volume	38
Nummer van het tijdschrift	15
DOI's	https://doi.org/10.1038/s41388-018-0595-3
Status	Gepubliceerd - 11 apr. 2019

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Claeys, S., Denecker, G., Durinck, K., Decaesteker, B., Mus, L. M., Loontiens, S., Vanhauwaert, S., Althoff, K., Wigerup, C., Bexell, D., Dolman, E., Henrich, K. O., Wehrmann, L., Westerhout, E. M., Demoulin, J. B., Kumps, C., Van Maerken, T., Laureys, G., Van Neste, C., ... Speleman, F. (2019). ALK positively regulates MYCN activity through repression of HBP1 expression. Oncogene, 38(15), 2690-2705. https://doi.org/10.1038/s41388-018-0595-3

@article{68109cae24084cab96a49fdf7678dedb,

title = "ALK positively regulates MYCN activity through repression of HBP1 expression",

abstract = " ALK mutations occur in 10% of primary neuroblastomas and represent a major target for precision treatment. In combination with MYCN amplification, ALK mutations infer an ultra-high-risk phenotype resulting in very poor patient prognosis. To open up opportunities for future precision drugging, a deeper understanding of the molecular consequences of constitutive ALK signaling and its relationship to MYCN activity in this aggressive pediatric tumor entity will be essential. We show that mutant ALK downregulates the {\textquoteleft}HMG-box transcription factor 1{\textquoteright} (HBP1) through the PI 3 K-AKT–FOXO3a signaling axis. HBP1 inhibits both the transcriptional activating and repressing activity of MYCN, the latter being mediated through PRC2 activity. HBP1 itself is under negative control of MYCN through miR-17~92. Combined targeting of HBP1 by PI 3 K antagonists and MYCN signaling by BET- or HDAC-inhibitors blocks MYCN activity and significantly reduces tumor growth, suggesting a novel targeted therapy option for high-risk neuroblastoma.",

author = "Shana Claeys and Geertrui Denecker and Kaat Durinck and Bieke Decaesteker and Mus, {Liselot M.} and Siebe Loontiens and Suzanne Vanhauwaert and Kristina Althoff and Caroline Wigerup and Daniel Bexell and Emmy Dolman and Henrich, {Kai Oliver} and Lea Wehrmann and Westerhout, {Ellen M.} and Demoulin, {Jean Baptiste} and Candy Kumps and {Van Maerken}, Tom and Genevieve Laureys and {Van Neste}, Christophe and {De Wilde}, Bram and {De Wever}, Olivier and Frank Westermann and Rogier Versteeg and Molenaar, {Jan J.} and Sven P{\aa}hlman and Schulte, {Johannes H.} and {De Preter}, Katleen and Frank Speleman",

note = "Publisher Copyright: {\textcopyright} 2018, Springer Nature Limited.",

year = "2019",

month = apr,

day = "11",

doi = "10.1038/s41388-018-0595-3",

language = "English",

volume = "38",

pages = "2690--2705",

journal = "Oncogene",

issn = "0950-9232",

publisher = "Springer Nature",

number = "15",

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Claeys, S, Denecker, G, Durinck, K, Decaesteker, B, Mus, LM, Loontiens, S, Vanhauwaert, S, Althoff, K, Wigerup, C, Bexell, D, Dolman, E, Henrich, KO, Wehrmann, L, Westerhout, EM, Demoulin, JB, Kumps, C, Van Maerken, T, Laureys, G, Van Neste, C, De Wilde, B, De Wever, O, Westermann, F, Versteeg, R, Molenaar, JJ, Påhlman, S, Schulte, JH, De Preter, K & Speleman, F 2019, 'ALK positively regulates MYCN activity through repression of HBP1 expression', Oncogene, vol. 38, nr. 15, blz. 2690-2705. https://doi.org/10.1038/s41388-018-0595-3

TY - JOUR

T1 - ALK positively regulates MYCN activity through repression of HBP1 expression

AU - Claeys, Shana

AU - Denecker, Geertrui

AU - Durinck, Kaat

AU - Decaesteker, Bieke

AU - Mus, Liselot M.

AU - Loontiens, Siebe

AU - Vanhauwaert, Suzanne

AU - Althoff, Kristina

AU - Wigerup, Caroline

AU - Bexell, Daniel

AU - Dolman, Emmy

AU - Henrich, Kai Oliver

AU - Wehrmann, Lea

AU - Westerhout, Ellen M.

AU - Demoulin, Jean Baptiste

AU - Kumps, Candy

AU - Van Maerken, Tom

AU - Laureys, Genevieve

AU - Van Neste, Christophe

AU - De Wilde, Bram

AU - De Wever, Olivier

AU - Westermann, Frank

AU - Versteeg, Rogier

AU - Molenaar, Jan J.

AU - Påhlman, Sven

AU - Schulte, Johannes H.

AU - De Preter, Katleen

AU - Speleman, Frank

PY - 2019/4/11

Y1 - 2019/4/11

N2 - ALK mutations occur in 10% of primary neuroblastomas and represent a major target for precision treatment. In combination with MYCN amplification, ALK mutations infer an ultra-high-risk phenotype resulting in very poor patient prognosis. To open up opportunities for future precision drugging, a deeper understanding of the molecular consequences of constitutive ALK signaling and its relationship to MYCN activity in this aggressive pediatric tumor entity will be essential. We show that mutant ALK downregulates the ‘HMG-box transcription factor 1’ (HBP1) through the PI 3 K-AKT–FOXO3a signaling axis. HBP1 inhibits both the transcriptional activating and repressing activity of MYCN, the latter being mediated through PRC2 activity. HBP1 itself is under negative control of MYCN through miR-17~92. Combined targeting of HBP1 by PI 3 K antagonists and MYCN signaling by BET- or HDAC-inhibitors blocks MYCN activity and significantly reduces tumor growth, suggesting a novel targeted therapy option for high-risk neuroblastoma.

AB - ALK mutations occur in 10% of primary neuroblastomas and represent a major target for precision treatment. In combination with MYCN amplification, ALK mutations infer an ultra-high-risk phenotype resulting in very poor patient prognosis. To open up opportunities for future precision drugging, a deeper understanding of the molecular consequences of constitutive ALK signaling and its relationship to MYCN activity in this aggressive pediatric tumor entity will be essential. We show that mutant ALK downregulates the ‘HMG-box transcription factor 1’ (HBP1) through the PI 3 K-AKT–FOXO3a signaling axis. HBP1 inhibits both the transcriptional activating and repressing activity of MYCN, the latter being mediated through PRC2 activity. HBP1 itself is under negative control of MYCN through miR-17~92. Combined targeting of HBP1 by PI 3 K antagonists and MYCN signaling by BET- or HDAC-inhibitors blocks MYCN activity and significantly reduces tumor growth, suggesting a novel targeted therapy option for high-risk neuroblastoma.

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U2 - 10.1038/s41388-018-0595-3

DO - 10.1038/s41388-018-0595-3

M3 - Article

C2 - 30538293

AN - SCOPUS:85058246022

SN - 0950-9232

VL - 38

SP - 2690

EP - 2705

JO - Oncogene

JF - Oncogene

IS - 15

ER -

ALK positively regulates MYCN activity through repression of HBP1 expression

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