LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression

Jan J. Molenaar; Raquel Domingo-Fernández; Marli E. Ebus; Sven Lindner; Jan Koster; Ksenija Drabek; Pieter Mestdagh; Peter van Sluis; Linda J. Valentijn; Johan van Nes; Marloes Broekmans; Franciska Haneveld; Richard Volckmann; Isabella Bray; Lukas Heukamp; Annika Sprüssel; Theresa Thor; Kristina Kieckbusch; Ludger Klein-Hitpass; Matthias Fischer; Jo Vandesompele; Alexander Schramm; Max M. van Noesel; Luigi Varesio; Frank Speleman; Angelika Eggert; Raymond L. Stallings; Huib N. Caron; Rogier Versteeg; Johannes H. Schulte

doi:https://doi.org/10.1038/ng.2436

LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression

Jan J. Molenaar, Raquel Domingo-Fernández, Marli E. Ebus, Sven Lindner, Jan Koster, Ksenija Drabek, Pieter Mestdagh, Peter van Sluis, Linda J. Valentijn, Johan van Nes, Marloes Broekmans, Franciska Haneveld, Richard Volckmann, Isabella Bray, Lukas Heukamp, Annika Sprüssel, Theresa Thor, Kristina Kieckbusch, Ludger Klein-Hitpass, Matthias FischerJo Vandesompele, Alexander Schramm, Max M. van Noesel, Luigi Varesio, Frank Speleman, Angelika Eggert, Raymond L. Stallings, Huib N. Caron, Rogier Versteeg, Johannes H. Schulte

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

316 Citations (Scopus)

Abstract

LIN28B regulates developmental processes by modulating microRNAs (miRNAs) of the let-7 family. A role for LIN28B in cancer has been proposed but has not been established in vivo. Here, we report that LIN28B showed genomic aberrations and extensive overexpression in high-risk neuroblastoma compared to several other tumor entities and normal tissues. High LIN28B expression was an independent risk factor for adverse outcome in neuroblastoma. LIN28B signaled through repression of the let-7 miRNAs and consequently resulted in elevated MYCN protein expression in neuroblastoma cells. LIN28B-let-7-MYCN signaling blocked differentiation of normal neuroblasts and neuroblastoma cells. These findings were fully recapitulated in a mouse model in which LIN28B expression in the sympathetic adrenergic lineage induced development of neuroblastomas marked by low let-7 miRNA levels and high MYCN protein expression. Interference with this pathway might offer therapeutic perspectives

Original language	English
Pages (from-to)	1199-1206
Journal	Nature Genetics
Volume	44
Issue number	11
DOIs	https://doi.org/10.1038/ng.2436
Publication status	Published - 2012

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https://doi.org/10.1038/ng.2436

Cite this

Molenaar, J. J., Domingo-Fernández, R., Ebus, M. E., Lindner, S., Koster, J., Drabek, K., Mestdagh, P., van Sluis, P., Valentijn, L. J., van Nes, J., Broekmans, M., Haneveld, F., Volckmann, R., Bray, I., Heukamp, L., Sprüssel, A., Thor, T., Kieckbusch, K., Klein-Hitpass, L., ... Schulte, J. H. (2012). LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression. Nature Genetics, 44(11), 1199-1206. https://doi.org/10.1038/ng.2436

@article{184ba50576e74613bff32536233c135f,

title = "LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression",

abstract = "LIN28B regulates developmental processes by modulating microRNAs (miRNAs) of the let-7 family. A role for LIN28B in cancer has been proposed but has not been established in vivo. Here, we report that LIN28B showed genomic aberrations and extensive overexpression in high-risk neuroblastoma compared to several other tumor entities and normal tissues. High LIN28B expression was an independent risk factor for adverse outcome in neuroblastoma. LIN28B signaled through repression of the let-7 miRNAs and consequently resulted in elevated MYCN protein expression in neuroblastoma cells. LIN28B-let-7-MYCN signaling blocked differentiation of normal neuroblasts and neuroblastoma cells. These findings were fully recapitulated in a mouse model in which LIN28B expression in the sympathetic adrenergic lineage induced development of neuroblastomas marked by low let-7 miRNA levels and high MYCN protein expression. Interference with this pathway might offer therapeutic perspectives",

author = "Molenaar, {Jan J.} and Raquel Domingo-Fern{\'a}ndez and Ebus, {Marli E.} and Sven Lindner and Jan Koster and Ksenija Drabek and Pieter Mestdagh and {van Sluis}, Peter and Valentijn, {Linda J.} and {van Nes}, Johan and Marloes Broekmans and Franciska Haneveld and Richard Volckmann and Isabella Bray and Lukas Heukamp and Annika Spr{\"u}ssel and Theresa Thor and Kristina Kieckbusch and Ludger Klein-Hitpass and Matthias Fischer and Jo Vandesompele and Alexander Schramm and {van Noesel}, {Max M.} and Luigi Varesio and Frank Speleman and Angelika Eggert and Stallings, {Raymond L.} and Caron, {Huib N.} and Rogier Versteeg and Schulte, {Johannes H.}",

year = "2012",

doi = "https://doi.org/10.1038/ng.2436",

language = "English",

volume = "44",

pages = "1199--1206",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "11",

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Molenaar, JJ, Domingo-Fernández, R, Ebus, ME, Lindner, S, Koster, J, Drabek, K, Mestdagh, P, van Sluis, P, Valentijn, LJ, van Nes, J, Broekmans, M, Haneveld, F , Volckmann, R, Bray, I, Heukamp, L, Sprüssel, A, Thor, T, Kieckbusch, K, Klein-Hitpass, L, Fischer, M, Vandesompele, J, Schramm, A, van Noesel, MM, Varesio, L, Speleman, F, Eggert, A, Stallings, RL, Caron, HN, Versteeg, R & Schulte, JH 2012, 'LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression', Nature Genetics, vol. 44, no. 11, pp. 1199-1206. https://doi.org/10.1038/ng.2436

TY - JOUR

T1 - LIN28B induces neuroblastoma and enhances MYCN levels via let-7 suppression

AU - Molenaar, Jan J.

AU - Domingo-Fernández, Raquel

AU - Ebus, Marli E.

AU - Lindner, Sven

AU - Koster, Jan

AU - Drabek, Ksenija

AU - Mestdagh, Pieter

AU - van Sluis, Peter

AU - Valentijn, Linda J.

AU - van Nes, Johan

AU - Broekmans, Marloes

AU - Haneveld, Franciska

AU - Volckmann, Richard

AU - Bray, Isabella

AU - Heukamp, Lukas

AU - Sprüssel, Annika

AU - Thor, Theresa

AU - Kieckbusch, Kristina

AU - Klein-Hitpass, Ludger

AU - Fischer, Matthias

AU - Vandesompele, Jo

AU - Schramm, Alexander

AU - van Noesel, Max M.

AU - Varesio, Luigi

AU - Speleman, Frank

AU - Eggert, Angelika

AU - Stallings, Raymond L.

AU - Caron, Huib N.

AU - Versteeg, Rogier

AU - Schulte, Johannes H.

PY - 2012

Y1 - 2012

N2 - LIN28B regulates developmental processes by modulating microRNAs (miRNAs) of the let-7 family. A role for LIN28B in cancer has been proposed but has not been established in vivo. Here, we report that LIN28B showed genomic aberrations and extensive overexpression in high-risk neuroblastoma compared to several other tumor entities and normal tissues. High LIN28B expression was an independent risk factor for adverse outcome in neuroblastoma. LIN28B signaled through repression of the let-7 miRNAs and consequently resulted in elevated MYCN protein expression in neuroblastoma cells. LIN28B-let-7-MYCN signaling blocked differentiation of normal neuroblasts and neuroblastoma cells. These findings were fully recapitulated in a mouse model in which LIN28B expression in the sympathetic adrenergic lineage induced development of neuroblastomas marked by low let-7 miRNA levels and high MYCN protein expression. Interference with this pathway might offer therapeutic perspectives

AB - LIN28B regulates developmental processes by modulating microRNAs (miRNAs) of the let-7 family. A role for LIN28B in cancer has been proposed but has not been established in vivo. Here, we report that LIN28B showed genomic aberrations and extensive overexpression in high-risk neuroblastoma compared to several other tumor entities and normal tissues. High LIN28B expression was an independent risk factor for adverse outcome in neuroblastoma. LIN28B signaled through repression of the let-7 miRNAs and consequently resulted in elevated MYCN protein expression in neuroblastoma cells. LIN28B-let-7-MYCN signaling blocked differentiation of normal neuroblasts and neuroblastoma cells. These findings were fully recapitulated in a mouse model in which LIN28B expression in the sympathetic adrenergic lineage induced development of neuroblastomas marked by low let-7 miRNA levels and high MYCN protein expression. Interference with this pathway might offer therapeutic perspectives

U2 - https://doi.org/10.1038/ng.2436

DO - https://doi.org/10.1038/ng.2436

M3 - Article

C2 - 23042116

SN - 1061-4036

VL - 44

SP - 1199

EP - 1206

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -