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

P. Sin-Chan; I. Mumal; T. Suwal; B. Ho; X. Fan; I. Singh; Y. Du; M. Lu; N. Patel; J. Torchia; D. Popovski; M. Fouladi; P. Guilhamon; J. R. Hansford; S. Leary; L. M. Hoffman; Levy J. M. Mulcahy; A. Lassaletta; P. Solano-Paez; E. Rivas; A. Reddy; G. Y. Gillespie; N. Gupta; Meter T. E. Van; H. Nakamura; Wong T. -T.; Ra Y. -S.; Kim S. -K.; Luca Massimi; R. G. Grundy; J. Fangusaro; D. Johnston; J. Chan; L. Lafay-Cousin; E. I. Hwang; Y. Wang; D. Catchpoole; J. Michaud; B. Ellezam; R. Ramanujachar; H. Lindsay; M. D. Taylor; C. E. Hawkins; E. Bouffet; N. Jabado; S. K. Singh; C. L. Kleinman; D. Barsyte-Lovejoy; Li X. -N.; P. B. Dirks; C. Y. Lin; S. C. Mack; J. N. Rich; A. 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

P. Sin-Chan
, I. Mumal
, T. Suwal
, B. Ho
, X. Fan
, I. Singh
, Y. Du
, M. Lu
, N. Patel
, J. Torchia
, D. Popovski
, M. Fouladi
, P. Guilhamon
, J. R. Hansford
, S. Leary
, L. M. Hoffman
, Levy J. M. Mulcahy
, A. Lassaletta
, P. Solano-Paez
, E. Rivas

A. Reddy, G. Y. Gillespie, N. Gupta, Meter T. E. Van, H. Nakamura, Wong T. -T., Ra Y. -S., Kim S. -K., Luca Massimi, R. G. Grundy, J. Fangusaro, D. Johnston, J. Chan, L. Lafay-Cousin, E. I. Hwang, Y. Wang, D. Catchpoole, J. Michaud, B. Ellezam, R. Ramanujachar, H. Lindsay, M. D. Taylor, C. E. Hawkins, E. Bouffet, N. Jabado, S. K. Singh, C. L. Kleinman, D. Barsyte-Lovejoy, Li X. -N., P. B. Dirks, C. Y. Lin, S. C. Mack, J. N. Rich, A. Huang^*

^*Corresponding author

Research output: Contribution to journal › Article

26 Citations (Scopus)

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.

Original language	English
Pages (from-to)	51-67.e7
Journal	Cancer Cell
Volume	36
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2019.06.002
Publication status	Published - 2019

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

All Science Journal Classification (ASJC) codes

Oncology
Cancer Research

Keywords

Biological
Biomarkers
Brain Neoplasms
C19MC
Cell Cycle
Cell Transformation
Chromosomes
DNA Copy Number Variations
ETMR
Enhancer Elements
Epigenesis
Gene Expression Regulation
Gene Regulatory Networks
Genetic
Genetic Association Studies
Genetic Predisposition to Disease
Germ Cell and Embryonal
Human
Humans
LIN28A
MYCN
MicroRNAs
Models
Multigene Family
N-Myc Proto-Oncogene Protein
Neoplasms
Neoplastic
Oncogenes
Pair 19
Pair 2
RNA-Binding Proteins
Tumor
brain tumor
cell-cycle
epigenetics
microRNA
super-enhancer
therapeutics

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10.1016/j.ccell.2019.06.002

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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, L. 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

@article{8ab1cd9d98e5460397dfe1d4f4a17478,

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 = "Biological, Biomarkers, Brain Neoplasms, C19MC, Cell Cycle, Cell Transformation, Chromosomes, DNA Copy Number Variations, ETMR, Enhancer Elements, Epigenesis, Gene Expression Regulation, Gene Regulatory Networks, Genetic, Genetic Association Studies, Genetic Predisposition to Disease, Germ Cell and Embryonal, Human, Humans, LIN28A, MYCN, MicroRNAs, Models, Multigene Family, N-Myc Proto-Oncogene Protein, Neoplasms, Neoplastic, Oncogenes, Pair 19, Pair 2, RNA-Binding Proteins, Tumor, brain tumor, cell-cycle, epigenetics, microRNA, super-enhancer, therapeutics, Biological, Biomarkers, Brain Neoplasms, C19MC, Cell Cycle, Cell Transformation, Chromosomes, DNA Copy Number Variations, ETMR, Enhancer Elements, Epigenesis, Gene Expression Regulation, Gene Regulatory Networks, Genetic, Genetic Association Studies, Genetic Predisposition to Disease, Germ Cell and Embryonal, Human, Humans, LIN28A, MYCN, MicroRNAs, Models, Multigene Family, N-Myc Proto-Oncogene Protein, Neoplasms, Neoplastic, Oncogenes, Pair 19, Pair 2, RNA-Binding Proteins, Tumor, brain tumor, cell-cycle, epigenetics, microRNA, super-enhancer, therapeutics",

author = "P. Sin-Chan and I. Mumal and T. Suwal and B. Ho and X. Fan and I. Singh and Y. Du and M. Lu and N. Patel and J. Torchia and D. Popovski and M. Fouladi and P. Guilhamon and Hansford, \{J. R.\} and S. Leary and Hoffman, \{L. M.\} and Mulcahy, \{Levy J. M.\} and A. Lassaletta and P. Solano-Paez and E. Rivas and A. Reddy and Gillespie, \{G. Y.\} and N. Gupta and Van, \{Meter T. E.\} and H. Nakamura and -T., \{Wong T.\} and -S., \{Ra Y.\} and -K., \{Kim S.\} and Luca Massimi and Grundy, \{R. G.\} and J. Fangusaro and D. Johnston and J. Chan and L. Lafay-Cousin and Hwang, \{E. I.\} and Y. Wang and D. Catchpoole and J. Michaud and B. Ellezam and R. Ramanujachar and H. Lindsay and Taylor, \{M. D.\} and Hawkins, \{C. E.\} and E. Bouffet and N. Jabado and Singh, \{S. K.\} and Kleinman, \{C. L.\} and D. Barsyte-Lovejoy and -N., \{Li X.\} and Dirks, \{P. B.\} and Lin, \{C. Y.\} and Mack, \{S. C.\} and Rich, \{J. N.\} and A. Huang",

year = "2019",

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",

}

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, LJM, Lassaletta, A, Solano-Paez, P, Rivas, E, Reddy, A, Gillespie, GY, Gupta, N, Van, MTE, Nakamura, H, -T., WT, -S., RY, -K., KS, 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, -N., LX, 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, vol. 36, no. 1, pp. 51-67.e7. https://doi.org/10.1016/j.ccell.2019.06.002

TY - JOUR

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

AU - Sin-Chan, P.

AU - Mumal, I.

AU - Suwal, T.

AU - Ho, B.

AU - Fan, X.

AU - Singh, I.

AU - Du, Y.

AU - Lu, M.

AU - Patel, N.

AU - Torchia, J.

AU - Popovski, D.

AU - Fouladi, M.

AU - Guilhamon, P.

AU - Hansford, J. R.

AU - Leary, S.

AU - Hoffman, L. M.

AU - Mulcahy, Levy J. M.

AU - Lassaletta, A.

AU - Solano-Paez, P.

AU - Rivas, E.

AU - Reddy, A.

AU - Gillespie, G. Y.

AU - Gupta, N.

AU - Van, Meter T. E.

AU - Nakamura, H.

AU - -T., Wong T.

AU - -S., Ra Y.

AU - -K., Kim S.

AU - Massimi, Luca

AU - Grundy, R. G.

AU - Fangusaro, J.

AU - Johnston, D.

AU - Chan, J.

AU - Lafay-Cousin, L.

AU - Hwang, E. I.

AU - Wang, Y.

AU - Catchpoole, D.

AU - Michaud, J.

AU - Ellezam, B.

AU - Ramanujachar, R.

AU - Lindsay, H.

AU - Taylor, M. D.

AU - Hawkins, C. E.

AU - Bouffet, E.

AU - Jabado, N.

AU - Singh, S. K.

AU - Kleinman, C. L.

AU - Barsyte-Lovejoy, D.

AU - -N., Li X.

AU - Dirks, P. B.

AU - Lin, C. Y.

AU - Mack, S. C.

AU - Rich, J. N.

AU - Huang, A.

PY - 2019

Y1 - 2019

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 - Biological

KW - Biomarkers

KW - Brain Neoplasms

KW - C19MC

KW - Cell Cycle

KW - Cell Transformation

KW - Chromosomes

KW - DNA Copy Number Variations

KW - ETMR

KW - Enhancer Elements

KW - Epigenesis

KW - Gene Expression Regulation

KW - Gene Regulatory Networks

KW - Genetic

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Germ Cell and Embryonal

KW - Human

KW - Humans

KW - LIN28A

KW - MYCN

KW - MicroRNAs

KW - Models

KW - Multigene Family

KW - N-Myc Proto-Oncogene Protein

KW - Neoplasms

KW - Neoplastic

KW - Oncogenes

KW - Pair 19

KW - Pair 2

KW - RNA-Binding Proteins

KW - Tumor

KW - brain tumor

KW - cell-cycle

KW - epigenetics

KW - microRNA

KW - super-enhancer

KW - therapeutics

KW - Biological

KW - Biomarkers

KW - Brain Neoplasms

KW - C19MC

KW - Cell Cycle

KW - Cell Transformation

KW - Chromosomes

KW - DNA Copy Number Variations

KW - ETMR

KW - Enhancer Elements

KW - Epigenesis

KW - Gene Expression Regulation

KW - Gene Regulatory Networks

KW - Genetic

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Germ Cell and Embryonal

KW - Human

KW - Humans

KW - LIN28A

KW - MYCN

KW - MicroRNAs

KW - Models

KW - Multigene Family

KW - N-Myc Proto-Oncogene Protein

KW - Neoplasms

KW - Neoplastic

KW - Oncogenes

KW - Pair 19

KW - Pair 2

KW - RNA-Binding Proteins

KW - Tumor

KW - brain tumor

KW - cell-cycle

KW - epigenetics

KW - microRNA

KW - super-enhancer

KW - therapeutics

UR - https://publicatt.unicatt.it/handle/10807/172310

UR - https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=85067898536&origin=inward

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85067898536&origin=inward

U2 - 10.1016/j.ccell.2019.06.002

DO - 10.1016/j.ccell.2019.06.002

M3 - Article

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

Abstract

UN SDGs

All Science Journal Classification (ASJC) codes

Keywords

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