A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor

Patrick Sin-Chan; Iqra Mumal; Tannu Suwal; Ben Ho; Xiaolian Fan; Irtisha Singh; Yuchen Du; Mei Lu; Neilket Patel; Jonathon Torchia; Dean Popovski; Maryam Fouladi; Paul Guilhamon; Jordan R. Hansford; Sarah Leary; Lindsey M. Hoffman; Jean M. Mulcahy Levy; Alvaro Lassaletta; Palma Solano-Paez; Eloy Rivas; Alyssa Reddy; G. Yancey Gillespie; Nalin Gupta; Timothy E. Van Meter; Hideo Nakamura; Tai Tong Wong; Young Shin Ra; Seung Ki Kim; Luca Massimi; Richard G. Grundy; Jason Fangusaro; Donna Johnston; Jennifer Chan; Lucie Lafay-Cousin; Eugene I. Hwang; Yin Wang; Daniel Catchpoole; Jean Michaud; Benjamin Ellezam; Ramya Ramanujachar; Holly Lindsay; Michael D. Taylor; Cynthia E. Hawkins; Eric Bouffet; Nada Jabado; Sheila K. Singh; Claudia L. Kleinman; Dalia Barsyte-Lovejoy; Xiao Nan Li; Peter B. Dirks; Charles Y. Lin; Stephen C. Mack; Jeremy N. Rich; Annie Huang

doi:10.1016/j.ccell.2019.06.002

A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor

Patrick Sin-Chan, Iqra Mumal, Tannu Suwal, Ben Ho, Xiaolian Fan, Irtisha Singh, Yuchen Du, Mei Lu, Neilket Patel, Jonathon Torchia, Dean Popovski, Maryam Fouladi, Paul Guilhamon, Jordan R. Hansford, Sarah Leary, Lindsey M. Hoffman, Jean M. Mulcahy Levy, Alvaro Lassaletta, Palma Solano-Paez, Eloy RivasAlyssa Reddy, G. Yancey Gillespie, Nalin Gupta, Timothy E. Van Meter, Hideo Nakamura, Tai Tong Wong, Young Shin Ra, Seung Ki Kim, Luca Massimi, Richard G. Grundy, Jason Fangusaro, Donna Johnston, Jennifer Chan, Lucie Lafay-Cousin, Eugene I. Hwang, Yin Wang, Daniel Catchpoole, Jean Michaud, Benjamin Ellezam, Ramya Ramanujachar, Holly Lindsay, Michael D. Taylor, Cynthia E. Hawkins, Eric Bouffet, Nada Jabado, Sheila K. Singh, Claudia L. Kleinman, Dalia Barsyte-Lovejoy, Xiao Nan Li, Peter B. Dirks, Charles Y. Lin, Stephen C. Mack, Jeremy N. Rich, Annie Huang

研究成果: 雜誌貢獻 › 文章 › 同行評審

57 引文斯高帕斯（Scopus）

摘要

Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death. Sin-Chan et al. uncover a C19MC-LIN28A-MYCN super-enhancer-dependent oncogenic circuit in embryonal tumors with multilayered rosettes (ETMRs). The circuit entraps an early neural lineage network to sustain embryonic epigenetic programming and is vulnerable to bromodomain inhibition, which promotes ETMR cell death.

原文	英語
頁（從 - 到）	51-67.e7
期刊	Cancer Cell
卷	36
發行號	1
DOIs	https://doi.org/10.1016/j.ccell.2019.06.002
出版狀態	已發佈 - 7月 8 2019

ASJC Scopus subject areas

腫瘤科
細胞生物學
癌症研究

UN SDG

此研究成果有助於以下永續發展目標

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10.1016/j.ccell.2019.06.002

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引用此

Sin-Chan, P., Mumal, I., Suwal, T., Ho, B., Fan, X., Singh, I., Du, Y., Lu, M., Patel, N., Torchia, J., Popovski, D., Fouladi, M., Guilhamon, P., Hansford, J. R., Leary, S., Hoffman, L. M., Mulcahy Levy, J. M., Lassaletta, A., Solano-Paez, P., ... Huang, A. (2019). A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor. Cancer Cell, 36(1), 51-67.e7. https://doi.org/10.1016/j.ccell.2019.06.002

Sin-Chan, P, Mumal, I, Suwal, T, Ho, B, Fan, X, Singh, I, Du, Y, Lu, M, Patel, N, Torchia, J, Popovski, D, Fouladi, M, Guilhamon, P, Hansford, JR, Leary, S, Hoffman, LM, Mulcahy Levy, JM, Lassaletta, A, Solano-Paez, P, Rivas, E, Reddy, A, Gillespie, GY, Gupta, N, Van Meter, TE, Nakamura, H, Wong, TT, Ra, YS, Kim, SK, Massimi, L, Grundy, RG, Fangusaro, J, Johnston, D, Chan, J, Lafay-Cousin, L, Hwang, EI, Wang, Y, Catchpoole, D, Michaud, J, Ellezam, B, Ramanujachar, R, Lindsay, H, Taylor, MD, Hawkins, CE, Bouffet, E, Jabado, N, Singh, SK, Kleinman, CL, Barsyte-Lovejoy, D, Li, XN, Dirks, PB, Lin, CY, Mack, SC, Rich, JN & Huang, A 2019, 'A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor', Cancer Cell, 卷 36, 編號 1, 頁 51-67.e7. https://doi.org/10.1016/j.ccell.2019.06.002

@article{e1f8c4b407b448478a39ea9cde452b6c,

title = "A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor",

abstract = "Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death. Sin-Chan et al. uncover a C19MC-LIN28A-MYCN super-enhancer-dependent oncogenic circuit in embryonal tumors with multilayered rosettes (ETMRs). The circuit entraps an early neural lineage network to sustain embryonic epigenetic programming and is vulnerable to bromodomain inhibition, which promotes ETMR cell death.",

keywords = "brain tumor, C19MC, cell-cycle, epigenetics, ETMR, LIN28A, microRNA, MYCN, super-enhancer, therapeutics",

author = "Patrick Sin-Chan and Iqra Mumal and Tannu Suwal and Ben Ho and Xiaolian Fan and Irtisha Singh and Yuchen Du and Mei Lu and Neilket Patel and Jonathon Torchia and Dean Popovski and Maryam Fouladi and Paul Guilhamon and Hansford, {Jordan R.} and Sarah Leary and Hoffman, {Lindsey M.} and {Mulcahy Levy}, {Jean M.} and Alvaro Lassaletta and Palma Solano-Paez and Eloy Rivas and Alyssa Reddy and Gillespie, {G. Yancey} and Nalin Gupta and {Van Meter}, {Timothy E.} and Hideo Nakamura and Wong, {Tai Tong} and Ra, {Young Shin} and Kim, {Seung Ki} and Luca Massimi and Grundy, {Richard G.} and Jason Fangusaro and Donna Johnston and Jennifer Chan and Lucie Lafay-Cousin and Hwang, {Eugene I.} and Yin Wang and Daniel Catchpoole and Jean Michaud and Benjamin Ellezam and Ramya Ramanujachar and Holly Lindsay and Taylor, {Michael D.} and Hawkins, {Cynthia E.} and Eric Bouffet and Nada Jabado and Singh, {Sheila K.} and Kleinman, {Claudia L.} and Dalia Barsyte-Lovejoy and Li, {Xiao Nan} and Dirks, {Peter B.} and Lin, {Charles Y.} and Mack, {Stephen C.} and Rich, {Jeremy N.} and Annie Huang",

note = "Funding Information: S. Krumholtz and J. Loukides for assistance with graphics and technical contributions, The Rare Brain Tumor Consortium ( http://www.rarebraintumorconsortium.ca ) and tumor banks of contributing centers for tumor tissue. This project was funded by a Canadian Institutes of Health Research (CIHR) grant no. 137011 and b.r.a.i.n. child to A.H. T.S. is a CIHR Scholar. Funding Information: S. Krumholtz and J. Loukides for assistance with graphics and technical contributions, The Rare Brain Tumor Consortium (http://www.rarebraintumorconsortium.ca) and tumor banks of contributing centers for tumor tissue. This project was funded by a Canadian Institutes of Health Research (CIHR) grant no. 137011 and b.r.a.i.n. child to A.H. T.S. is a CIHR Scholar. A.H. conceived and supervised all of the experiments except for ChIP-seq analyses, which was supervised by J.N.R. RNA-seq, gene expression, NanoString, and copy-number analyses were performed by P.S.-C. I.M. T.S. B.H. N.P. and J.T. ATAC and ChIP assays were performed by P.S.-C. X.F. and S.C.M. and data analyses were performed by P.S.-C. I.M. and N.P. with advice from P.G. and S.C.M. CRC analyses was performed by I.M. and I.S. under supervision of C.Y.L. and A.H. Cellular, histopathologic, and biochemical assays were performed by P.S.-C. I.M. T.S. M.L. and D.P. Statistical analyses was performed by P.S.-C. I.M. and T.S. Tumor tissue and cell lines used in this study were provided by M.F. A.L. P.S.-P. E.R. L.M.H. N.G. T.E.V.M. S.L. H.N. T.-T.W. Y.-S.R. S.-K.K. L.M. R.G.G. J.F. D.J. J.C. L.L.-C. E.I.H. Y.W. A.R. G.Y.G. D.C. J.R.H. J.M. J.M.M.L. B.E. R.R. H.L. N.J. C.L.K. M.D.T. C.E.H. E.B. P.B.D. S.K.S. X.N.-L. and Y.D. D.B.-L. provided JQ1. P.S.-C. I.M. and A.H. wrote the manuscript with input from J.N.R. and S.C.M. P.S.-C. is employed at Regeneron Pharmaceuticals. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

year = "2019",

month = jul,

day = "8",

doi = "10.1016/j.ccell.2019.06.002",

language = "English",

volume = "36",

pages = "51--67.e7",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "1",

}

TY - JOUR

T1 - A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs

T2 - A Lethal Brain Tumor

AU - Sin-Chan, Patrick

AU - Mumal, Iqra

AU - Suwal, Tannu

AU - Ho, Ben

AU - Fan, Xiaolian

AU - Singh, Irtisha

AU - Du, Yuchen

AU - Lu, Mei

AU - Patel, Neilket

AU - Torchia, Jonathon

AU - Popovski, Dean

AU - Fouladi, Maryam

AU - Guilhamon, Paul

AU - Hansford, Jordan R.

AU - Leary, Sarah

AU - Hoffman, Lindsey M.

AU - Mulcahy Levy, Jean M.

AU - Lassaletta, Alvaro

AU - Solano-Paez, Palma

AU - Rivas, Eloy

AU - Reddy, Alyssa

AU - Gillespie, G. Yancey

AU - Gupta, Nalin

AU - Van Meter, Timothy E.

AU - Nakamura, Hideo

AU - Wong, Tai Tong

AU - Ra, Young Shin

AU - Kim, Seung Ki

AU - Massimi, Luca

AU - Grundy, Richard G.

AU - Fangusaro, Jason

AU - Johnston, Donna

AU - Chan, Jennifer

AU - Lafay-Cousin, Lucie

AU - Hwang, Eugene I.

AU - Wang, Yin

AU - Catchpoole, Daniel

AU - Michaud, Jean

AU - Ellezam, Benjamin

AU - Ramanujachar, Ramya

AU - Lindsay, Holly

AU - Taylor, Michael D.

AU - Hawkins, Cynthia E.

AU - Bouffet, Eric

AU - Jabado, Nada

AU - Singh, Sheila K.

AU - Kleinman, Claudia L.

AU - Barsyte-Lovejoy, Dalia

AU - Li, Xiao Nan

AU - Dirks, Peter B.

AU - Lin, Charles Y.

AU - Mack, Stephen C.

AU - Rich, Jeremy N.

AU - Huang, Annie

N1 - Funding Information: S. Krumholtz and J. Loukides for assistance with graphics and technical contributions, The Rare Brain Tumor Consortium ( http://www.rarebraintumorconsortium.ca ) and tumor banks of contributing centers for tumor tissue. This project was funded by a Canadian Institutes of Health Research (CIHR) grant no. 137011 and b.r.a.i.n. child to A.H. T.S. is a CIHR Scholar. Funding Information: S. Krumholtz and J. Loukides for assistance with graphics and technical contributions, The Rare Brain Tumor Consortium (http://www.rarebraintumorconsortium.ca) and tumor banks of contributing centers for tumor tissue. This project was funded by a Canadian Institutes of Health Research (CIHR) grant no. 137011 and b.r.a.i.n. child to A.H. T.S. is a CIHR Scholar. A.H. conceived and supervised all of the experiments except for ChIP-seq analyses, which was supervised by J.N.R. RNA-seq, gene expression, NanoString, and copy-number analyses were performed by P.S.-C. I.M. T.S. B.H. N.P. and J.T. ATAC and ChIP assays were performed by P.S.-C. X.F. and S.C.M. and data analyses were performed by P.S.-C. I.M. and N.P. with advice from P.G. and S.C.M. CRC analyses was performed by I.M. and I.S. under supervision of C.Y.L. and A.H. Cellular, histopathologic, and biochemical assays were performed by P.S.-C. I.M. T.S. M.L. and D.P. Statistical analyses was performed by P.S.-C. I.M. and T.S. Tumor tissue and cell lines used in this study were provided by M.F. A.L. P.S.-P. E.R. L.M.H. N.G. T.E.V.M. S.L. H.N. T.-T.W. Y.-S.R. S.-K.K. L.M. R.G.G. J.F. D.J. J.C. L.L.-C. E.I.H. Y.W. A.R. G.Y.G. D.C. J.R.H. J.M. J.M.M.L. B.E. R.R. H.L. N.J. C.L.K. M.D.T. C.E.H. E.B. P.B.D. S.K.S. X.N.-L. and Y.D. D.B.-L. provided JQ1. P.S.-C. I.M. and A.H. wrote the manuscript with input from J.N.R. and S.C.M. P.S.-C. is employed at Regeneron Pharmaceuticals. Publisher Copyright: © 2019 Elsevier Inc.

PY - 2019/7/8

Y1 - 2019/7/8

N2 - Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death. Sin-Chan et al. uncover a C19MC-LIN28A-MYCN super-enhancer-dependent oncogenic circuit in embryonal tumors with multilayered rosettes (ETMRs). The circuit entraps an early neural lineage network to sustain embryonic epigenetic programming and is vulnerable to bromodomain inhibition, which promotes ETMR cell death.

AB - Embryonal tumors with multilayered rosettes (ETMRs) are highly lethal infant brain cancers with characteristic amplification of Chr19q13.41 miRNA cluster (C19MC) and enrichment of pluripotency factor LIN28A. Here we investigated C19MC oncogenic mechanisms and discovered a C19MC-LIN28A-MYCN circuit fueled by multiple complex regulatory loops including an MYCN core transcriptional network and super-enhancers resulting from long-range MYCN DNA interactions and C19MC gene fusions. Our data show that this powerful oncogenic circuit, which entraps an early neural lineage network, is potently abrogated by bromodomain inhibitor JQ1, leading to ETMR cell death. Sin-Chan et al. uncover a C19MC-LIN28A-MYCN super-enhancer-dependent oncogenic circuit in embryonal tumors with multilayered rosettes (ETMRs). The circuit entraps an early neural lineage network to sustain embryonic epigenetic programming and is vulnerable to bromodomain inhibition, which promotes ETMR cell death.

KW - brain tumor

KW - C19MC

KW - cell-cycle

KW - epigenetics

KW - ETMR

KW - LIN28A

KW - microRNA

KW - MYCN

KW - super-enhancer

KW - therapeutics

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U2 - 10.1016/j.ccell.2019.06.002

DO - 10.1016/j.ccell.2019.06.002

M3 - Article

C2 - 31287992

AN - SCOPUS:85067898536

SN - 1535-6108

VL - 36

SP - 51-67.e7

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

A C19MC-LIN28A-MYCN Oncogenic Circuit Driven by Hijacked Super-enhancers Is a Distinct Therapeutic Vulnerability in ETMRs: A Lethal Brain Tumor

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ASJC Scopus subject areas

UN SDG

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