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

被引：68

作者：

Sin-Chan, Patrick ^{[1
]}

Mumal, Iqra ^{[1
,2
]}

Suwal, Tannu ^{[1
,2
]}

Ho, Ben ^{[1
]}

Fan, Xiaolian ^{[1
]}

Singh, Irtisha ^{[3
]}

Du, Yuchen ^{[4
]}

Lu, Mei ^{[1
]}

Patel, Neilket ^{[1
]}

Torchia, Jonathon ^{[5
]}

Popovski, Dean ^{[1
]}

Fouladi, Maryam ^{[6
]}

Guilhamon, Paul ^{[7
,8
]}

Hansford, Jordan R. ^{[9
]}

Leary, Sarah ^{[10
]}

Hoffman, Lindsey M. ^{[11
]}

Levy, Jean M. Mulcahy ^{[11
]}

Lassaletta, Alvaro ^{[12
]}

Solano-Paez, Palma ^{[13
]}

Rivas, Eloy ^{[14
]}

Reddy, Alyssa ^{[15
]}

Gillespie, G. Yancey ^{[16
]}

Gupta, Nalin ^{[17
]}

Van Meter, Timothy E. ^{[18
]}

Nakamura, Hideo ^{[19
]}

Wong, Tai-Tong ^{[20
]}

Ra, Young-Shin ^{[21
]}

Kim, Seung-Ki ^{[22
]}

Massimi, Luca ^{[23
]}

Grundy, Richard G. ^{[24
]}

Fangusaro, Jason ^{[25
,26
]}

Johnston, Donna ^{[27
]}

Chan, Jennifer ^{[28
]}

Lafay-Cousin, Lucie ^{[29
]}

Hwang, Eugene I. ^{[30
]}

Wang, Yin ^{[31
]}

Catchpoole, Daniel ^{[32
]}

Michaud, Jean ^{[33
]}

Ellezam, Benjamin ^{[34
]}

Ramanujachar, Ramya ^{[35
]}

Lindsay, Holly ^{[4
]}

Taylor, Michael D. ^{[2
,36
]}

Hawkins, Cynthia E. ^{[2
,37
]}

Bouffet, Eric ^{[38
]}

Jabado, Nada ^{[39
,40
]}

Singh, Sheila K. ^{[41
]}

Kleinman, Claudia L. ^{[39
,40
]}

Barsyte-Lovejoy, Dalia ^{[42
]}

Li, Xiao-Nan ^{[4
,43
]}

Dirks, Peter B. ^{[2
,36
]}

机构：

[1] Hosp Sick Children, Div Haematol Oncol, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON M5G 0A4, Canada

[2] Univ Toronto, Fac Med, Dept Lab Med & Pathobiol, Toronto, ON M5S 1A8, Canada

[3] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[4] Texas Childrens Hosp, Baylor Coll Med, Div Hematol & Oncol, Dept Pediat, Houston, TX 77030 USA

[5] Ontario Inst Canc Res, OICR Translat Genom Lab, Princess Margaret Canc Ctr, Toronto, ON M5G 0A3, Canada

[6] Cincinnati Childrens Hosp, Dept Canc & Blood Dis, Div Oncol, Cincinnati, OH 45229 USA

[7] Hosp Sick Children, Dev & Stem Cell Biol Program, Toronto, ON M5G 0A4, Canada

[8] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON M5G 0A4, Canada

[9] Univ Melbourne, Dept Pediat, Murdoch Childrens Res Inst, Childrens Canc Ctr,Royal Childrens Hosp, Melbourne, Vic 3052, Australia

[10] Seattle Childrens Hosp, Dept Hematol Oncol, Seattle, WA 98105 USA

[11] Univ Colorado Denver, Dept Pediat, Aurora, CO 80045 USA

[12] Hosp Infantil Univ Nino Jesus, Pediat Hematol & Oncol Dept, Madrid 28009, Spain

[13] Hosp Infantil Virgen del Rocio, Dept Pediat Oncol, Seville 41013, Spain

[14] Hosp Univ Virgen del Rocio, Div Neuropathol, Dept Pathol, Seville 41013, Spain

[15] Univ Alabama Birmingham, Birmingham, AL 35294 USA

[16] Univ Alabama Birmingham, Dept Neurosurg, Birmingham, AL 35294 USA

[17] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA

[18] Virginia Commonwealth Univ, Dept Pediat, Richmond, VA 23298 USA

[19] Kurume Univ, Dept Neurosurg, Fukuoka, Fukuoka 8300011, Japan

[20] Taipei Med Univ, Taipei Canc Ctr, Pediat Brain Tumor Program, Taipei 11031, Taiwan

[21] Asan Med Ctr, Dept Neurosurg, Seoul 138736, South Korea

[22] Seoul Natl Univ, Childrens Hosp, Div Pediat Neurosur, Seoul 03080, South Korea

[23] Univ Cattolica Sacro Cuore, Fdn Policlin A Gemelli IRCCS, Dept Neurosurg, I-00168 Rome, Italy

[24] Univ Nottingham, Queens Med Ctr, Childrens Brain Tumor Res Ctr, Nottingham NG7 2UH, England

[25] Childrens Healthcare Atlanta, Dept Pediat Hematol & Oncol, Atlanta, GA 30322 USA

[26] Emory Univ, Sch Med, Atlanta, GA 30322 USA

[27] Childrens Hosp Eastern Ontario, Div Hematol Oncol, Ottawa, ON K1H 8L1, Canada

[28] Univ Calgary, Dept Pathol & Lab Med, Calgary, AB T2N 1N4, Canada

[29] Alberta Childrens Prov Gen Hosp, Dept Pediat Oncol, Calgary, AB T3B 6A8, Canada

[30] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA

[31] Fudan Univ, Huashan Hosp, Dept Neuropathol, Shanghai 200040, Peoples R China

[32] Childrens Hosp Westmead, Kids Res, Tumor Bank, Childrens Canc Res Unit, Westmead, NSW 2145, Australia

[33] Univ Ottawa, Dept Pathol & Lab Med, Ottawa, ON K1H 8M5, Canada

[34] Univ Montreal, CHU St Justine Res Ctr, Dept Pathol, Montreal, PQ H3T 1C5, Canada

[35] Southampton Childrens Hosp, Paediat Haematol & Oncol, Southampton SO16 6YD, Hants, England

[36] Hosp Sick Children, Div Neurosurg, Arthur & Sonia Labatt Brain Tumor Res Ctr, Toronto, ON M5G 0A4, Canada

[37] Hosp Sick Children, Dept Pathol, Toronto, ON M5G 1X8, Canada

[38] Univ Toronto, Dept Pediat, Hosp Sick Children, Div Hematol Oncol, Toronto, ON M5G 0A4, Canada

[39] McGill Univ, Dept Pediat, Montreal, PQ H3A 0C7, Canada

[40] McGill Univ, Dept Human Genet, Montreal, PQ H3A 0C7, Canada

[41] McMaster Univ, McMaster Stem Cell & Canc Res Inst, Hamilton, ON L8S 4K1, Canada

[42] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L7, Canada

[43] Northwestern Univ, Feinberg Sch Med, Dept Pediat, Chicago, IL 60611 USA

[44] Univ Calif San Diego, Div Regenerat Med, Dept Med, San Diego, CA 92093 USA

[45] Univ Toronto, Fac Med, Dept Med Biophys, Toronto, ON M5G 1L7, Canada

来源：

CANCER CELL | 2019年 / 36卷 / 01期

基金：

加拿大健康研究院;

关键词：

EMBRYONAL TUMOR; WEB SERVER; EXPRESSION; MEDULLOBLASTOMA; METHYLATION; LET-7; FAMILY; TRISTETRAPROLIN; CLASSIFICATION; IDENTIFICATION;

D O I：

10.1016/j.ccell.2019.06.002

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

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.

引用

页码：51 / +

页数：24

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