Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma

被引：40

作者：

Bandopadhayay, Pratiti ^{[1
,2
,3
]}

Piccioni, Federica ^{[2
]}

O'Rourke, Ryan ^{[1
,2
]}

Ho, Patricia ^{[1
,2
]}

Gonzalez, Elizabeth M. ^{[1
,2
]}

Buchan, Graham ^{[1
,2
]}

Qian, Kenin ^{[1
,2
]}

Gionet, Gabrielle ^{[1
,2
]}

Girard, Emily ^{[4
]}

Coxon, Margo ^{[4
]}

Rees, Matthew G. ^{[2
]}

Brenan, Lisa ^{[2
]}

Dubois, Frank ^{[2
,5
]}

Shapira, Ofer ^{[2
,5
]}

Greenwald, Noah F. ^{[2
,5
,6
]}

Pages, Melanie ^{[1
,2
]}

Iniguez, Amanda Balboni ^{[1
,2
]}

Paolella, Brenton R. ^{[2
,5
]}

Meng, Alice ^{[7
]}

Sinai, Claire ^{[1
,7
]}

Roti, Giovanni ^{[1
,2
,8
]}

Dharia, Neekesh V. ^{[1
,2
,3
]}

Creech, Amanda ^{[2
]}

Tanenbaum, Benjamin ^{[2
]}

Khadka, Prasidda ^{[1
,2
,3
]}

Tracy, Adam ^{[2
]}

Tiv, Hong L. ^{[9
,10
]}

Hong, Andrew L. ^{[1
,2
,3
]}

Coy, Shannon ^{[11
]}

Rashid, Rumana ^{[11
,12
]}

Lin, Jia-Ren ^{[13
,14
]}

Cowley, Glenn S. ^{[2
,15
]}

Lam, Fred C. ^{[16
]}

Goodale, Amy ^{[2
]}

Lee, Yenarae ^{[2
]}

Schoolcraft, Kathleen ^{[7
]}

Vazquez, Francisca ^{[2
]}

Hahn, William C. ^{[2
,7
,17
]}

Tsherniak, Aviad ^{[2
]}

Bradner, James E. ^{[2
,7
,17
,18
]}

Yaffe, Michael B. ^{[2
,16
]}

Milde, Till ^{[19
,20
,21
]}

Pfister, Stefan M. ^{[19
,22
,23
,24
]}

Qi, Jun ^{[5
]}

Schenone, Monica ^{[2
]}

Carr, Steven A. ^{[2
]}

Ligon, Keith L. ^{[2
,11
,17
,25
,26
]}

Kieran, Mark W. ^{[1
,3
]}

Santagata, Sandro ^{[7
,11
]}

Olson, James M. ^{[4
]}

机构：

[1] Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA

[2] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[3] Harvard Med Sch, Dept Pediat, Boston, MA 02115 USA

[4] Fred Hutchinson Canc Res Ctr, Div Clin Res, 1124 Columbia St, Seattle, WA 98104 USA

[5] Dana Farber Canc Inst, Div Canc Biol, Boston, MA 02115 USA

[6] Brigham & Womens Hosp, Dept Neurosurg, 75 Francis St, Boston, MA 02115 USA

[7] Dana Farber Canc Inst, Div Med Oncol, Boston, MA 02115 USA

[8] Univ Parma, Dept Med & Surg Hematol & BMT, Parma, Italy

[9] Expt Therapeut Core, Boston, MA USA

[10] Belfer Ctr Appl Canc Sci, Boston, MA USA

[11] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA

[12] Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA

[13] Harvard Med Sch, Lab Syst Pharmacol, Boston, MA 02115 USA

[14] Harvard Med Sch, Ludwig Ctr Canc Res Harvard, Boston, MA 02115 USA

[15] Johnson & Johnson, Janssen Res & Dev, Discovery Sci, Spring House, PA USA

[16] MIT, Koch Inst Integrat Canc Res, Cambridge, MA 02139 USA

[17] Harvard Med Sch, Dept Med, Boston, MA 02115 USA

[18] Novartis Inst Biomed Res, Basel, Switzerland

[19] Hopp Childrens Canc Ctr Heidelberg KiTZ, Heidelberg, Germany

[20] German Canc Res Ctr, CCU Pediat Oncol, Heidelberg, Germany

[21] Heidelberg Univ Hosp, Ctr Child & Adolescent Med, Dept Pediat Oncol Hematol & Immunol, Heidelberg, Germany

[22] German Canc Consortium DKTK, Div Pediat Neurooncol, Heidelberg, Germany

[23] German Canc Res Ctr, Heidelberg, Germany

[24] Heidelberg Univ Hosp, Dept Pediat Hematol & Oncol, Heidelberg, Germany

[25] Dana Farber Canc Inst, Dept Oncol Pathol, Boston, MA 02115 USA

[26] Boston Childrens Hosp, Dept Pathol, Boston, MA USA

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

CANCER-CELLS; SENSITIVITY; TRANSCRIPTION; RESISTANCE; TUMORS; NEUROBLASTOMA; PROLIFERATION; CONNECTIVITY; PLASTICITY; STATE;

D O I：

10.1038/s41467-019-10307-9

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

BET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms for its action, and ultimately for resistance, have not been fully defined. Here, using a combination of expression profiling, genome-scale CRISPR/Cas9-mediated loss of function and ORF/cDNA driven rescue screens, and cell-based models of spontaneous resistance, we identify bHLH/homeobox transcription factors and cell-cycle regulators as key genes mediating BETi's response and resistance. Cells that acquire drug tolerance exhibit a more neuronally differentiated cell-state and expression of lineage-specific bHLH/homeobox transcription factors. However, they do not terminally differentiate, maintain expression of CCND2, and continue to cycle through S-phase. Moreover, CDK4/CDK6 inhibition delays acquisition of resistance. Therefore, our data provide insights about the mechanisms underlying BETi effects and the appearance of resistance and support the therapeutic use of combined cell-cycle inhibitors with BETi in MYC-amplified medulloblastoma.

引用

页数：16

共 61 条

[31] Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas [J].

Kool, Marcel ;

Korshunov, Andrey ;

Remke, Marc ;

Jones, David T. W. ;

Schlanstein, Maria ;

Northcott, Paul A. ;

Cho, Yoon-Jae ;

Koster, Jan ;

Schouten-van Meeteren, Antoinette ;

van Vuurden, Dannis ;

Clifford, Steven C. ;

Pietsch, Torsten ;

von Bueren, Andre O. ;

Rutkowski, Stefan ;

McCabe, Martin ;

Collins, V. Peter ;

Backlund, Magnus L. ;

Haberler, Christine ;

Bourdeaut, Franck ;

Delattre, Olivier ;

Doz, Francois ;

Ellison, David W. ;

Gilbertson, Richard J. ;

Pomeroy, Scott L. ;

Taylor, Michael D. ;

Lichter, Peter ;

Pfister, Stefan M. .

ACTA NEUROPATHOLOGICA, 2012, 123 (04) :473-484

[32] GLI2-dependent c-MYC upregulation mediates resistance of pancreatic cancer cells to the BET bromodomain inhibitor JQ1 [J].

Kumar, Krishan ;

Raza, Sania S. ;

Knab, Lawrence M. ;

Chow, Christina R. ;

Kwok, Benjamin ;

Bentrem, David J. ;

Popovic, Relja ;

Ebine, Kazumi ;

Licht, Jonathan D. ;

Munshi, Hidayatullah G. .

SCIENTIFIC REPORTS, 2015, 5

[33] BET bromodomain inhibition promotes neurogenesis while inhibiting gliogenesis in neural progenitor cells [J].

Li, Jingjun ;

Ma, Jing ;

Meng, Guofeng ;

Lin, Hong ;

Wu, Sharon ;

Wang, Jamie ;

Luo, Jie ;

Xu, Xiaohong ;

Tough, David ;

Lindon, Matthew ;

Rioja, Inmaculada ;

Zhao, Jing ;

Mei, Hongkang ;

Prinjha, Rab ;

Zhong, Zhong .

STEM CELL RESEARCH, 2016, 17 (02) :212-221

[34] Genetic modifiers of the BRD4-NUT dependency of NUT midline carcinoma uncovers a synergism between BETis and CDK4/6is [J].

Liao, Sida ;

Maertens, Ophelia ;

Cichowski, Karen ;

Elledge, Stephen J. .

GENES & DEVELOPMENT, 2018, 32 (17-18) :1188-1200

[35] Adaptive Chromatin Remodeling Drives Glioblastoma Stem Cell Plasticity and Drug Tolerance [J].

Liau, Brian B. ;

Sievers, Cem ;

Donohue, Laura K. ;

Gillespie, Shawn M. ;

Flavahan, William A. ;

Miller, Tyler E. ;

Venteicher, Andrew S. ;

Hebert, Christine H. ;

Carey, Christopher D. ;

Rodig, Scott J. ;

Shareef, Sarah J. ;

Najm, Fadi J. ;

van Galen, Peter ;

Wakimoto, Hiroaki ;

Cahill, Daniel P. ;

Rich, Jeremy N. ;

Aster, Jon C. ;

Suva, Mario L. ;

Patel, Anoop P. ;

Bernstein, Bradley E. .

CELL STEM CELL, 2017, 20 (02) :233-+

[36] Highly multiplexed imaging of single cells using a high-throughput cyclic immunofluorescence method [J].

Lin, Jia-Ren ;

Fallahi-Sichani, Mohammad ;

Sorger, Peter K. .

NATURE COMMUNICATIONS, 2015, 6

[37]

Meyers R. M, 2017, NAT GENET, V350, P1096

[38] HD-MB03 is a novel Group 3 medulloblastoma model demonstrating sensitivity to histone deacetylase inhibitor treatment [J].

Milde, Till ;

Lodrini, Marco ;

Savelyeva, Larissa ;

Korshunov, Andrey ;

Kool, Marcel ;

Brueckner, Lena M. ;

Antunes, Andre S. L. M. ;

Oehme, Ina ;

Pekrun, Arnulf ;

Pfister, Stefan M. ;

Kulozik, Andreas E. ;

Witt, Olaf ;

Deubzer, Hedwig E. .

JOURNAL OF NEURO-ONCOLOGY, 2012, 110 (03) :335-348

[39] Bromodomain and Extra-terminal (BET) Protein Inhibitors Suppress Chondrocyte Differentiation and Restrain Bone Growth [J].

Niu, Ningning ;

Shao, Rui ;

Yan, Guang ;

Zou, Weiguo .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2016, 291 (52) :26647-26657

[40] Medulloblastoma Comprises Four Distinct Molecular Variants [J].

Northcott, Paul A. ;

Korshunov, Andrey ;

Witt, Hendrik ;

Hielscher, Thomas ;

Eberhart, Charles G. ;

Mack, Stephen ;

Bouffet, Eric ;

Clifford, Steven C. ;

Hawkins, Cynthia E. ;

French, Pim ;

Rutka, James T. ;

Pfister, Stefan ;

Taylor, Michael D. .

JOURNAL OF CLINICAL ONCOLOGY, 2011, 29 (11) :1408-1414

← 1 2 3 4 5 6 7 →