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

[1] MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism [J].

Bandopadhayay, Pratiti ;

Ramkissoon, Lori A. ;

Jain, Payal ;

Bergthold, Guillaume ;

Wala, Jeremiah ;

Zeid, Rhamy ;

Schumacher, Steven E. ;

Urbanski, Laura ;

O'Rourke, Ryan ;

Gibson, William J. ;

Pelton, Kristine ;

Ramkissoon, Shakti H. ;

Han, Harry J. ;

Zhu, Yuankun ;

Choudhari, Namrata ;

Silva, Amanda ;

Boucher, Katie ;

Henn, Rosemary E. ;

Kang, Yun Jee ;

Knoff, David ;

Paolella, Brenton R. ;

Gladden-Young, Adrianne ;

Varlet, Pascale ;

Pages, Melanie ;

Horowitz, Peleg M. ;

Federation, Alexander ;

Malkin, Hayley ;

Tracy, Adam A. ;

Seepo, Sara ;

Ducar, Matthew ;

Van Hummelen, Paul ;

Santi, Mariarita ;

Buccoliero, Anna Maria ;

Scagnet, Mirko ;

Bowers, Daniel C. ;

Giannini, Caterina ;

Puget, Stephanie ;

Hawkins, Cynthia ;

Tabori, Uri ;

Klekner, Almos ;

Bognar, Laszlo ;

Burger, Peter C. ;

Eberhart, Charles ;

Rodriguez, Fausto J. ;

Hill, D. Ashley ;

Mueller, Sabine ;

Haas-Kogan, Daphne A. ;

Phillips, Joanna J. ;

Santagata, Sandro ;

Stiles, Charles D. .

NATURE GENETICS, 2016, 48 (03) :273-282

[2] BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma [J].

Bandopadhayay, Pratiti ;

Bergthold, Guillaume ;

Nguyen, Brian ;

Schubert, Simone ;

Gholamin, Sharareh ;

Tang, Yujie ;

Bolin, Sara ;

Schumacher, Steven E. ;

Zeid, Rhamy ;

Masoud, Sabran ;

Yu, Furong ;

Vue, Nujsaubnusi ;

Gibson, William J. ;

Paolella, Brenton R. ;

Mitra, Siddhartha S. ;

Cheshier, Samuel H. ;

Qi, Jun ;

Liu, Kun-Wei ;

Wechsler-Reya, Robert ;

Weiss, William A. ;

Swartling, Fredrik J. ;

Kieran, Mark W. ;

Bradner, James E. ;

Beroukhim, Rameen ;

Cho, Yoon-Jae .

CLINICAL CANCER RESEARCH, 2014, 20 (04) :912-925

[3] MyoD and the transcriptional control of myogenesis [J].

Berkes, CA ;

Tapscott, SJ .

SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY, 2005, 16 (4-5) :585-595

[4] The toxicity of poisons applied jointly [J].

Bliss, CI .

ANNALS OF APPLIED BIOLOGY, 1939, 26 (03) :585-615

[5] Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma [J].

Bolin, Sara ;

Borgenvik, Anna ;

Persson, Camilla U. ;

Sundstrom, Anders ;

Qi, Jun ;

Bradner, James E. ;

Weiss, William A. ;

Cho, Yoon-Jae ;

Weishaupt, Holger ;

Swartling, Fredrik J. .

ONCOGENE, 2018, 37 (21) :2850-2862

[6] A comparison of normalization methods for high density oligonucleotide array data based on variance and bias [J].

Bolstad, BM ;

Irizarry, RA ;

Åstrand, M ;

Speed, TP .

BIOINFORMATICS, 2003, 19 (02) :185-193

[7] A biobank of patient-derived pediatric brain tumor models [J].

Brabetz, Sebastian ;

Leary, Sarah E. S. ;

Groebner, Susanne N. ;

Nakamoto, Madison W. ;

Seker-Cin, Huriye ;

Girard, Emily J. ;

Cole, Bonnie ;

Strand, Andrew D. ;

Bloom, Karina L. ;

Hovestadt, Volker ;

Mack, Norman L. ;

Pakiam, Fiona ;

Schwalm, Benjamin ;

Korshunov, Andrey ;

Balasubramanian, Gnana Prakash ;

Northcott, Paul A. ;

Pedro, Kyle D. ;

Dey, Joyoti ;

Hansen, Stacey ;

Ditzler, Sally ;

Lichter, Peter ;

Chavez, Lukas ;

Jones, David T. W. ;

Koster, Jan ;

Pfister, Stefan M. ;

Kool, Marcel ;

Olson, James M. .

NATURE MEDICINE, 2018, 24 (11) :1752-+

[8] BET bromodomain proteins regulate enhancer function during adipogenesis [J].

Brown, Jonathan D. ;

Feldman, Zachary B. ;

Doherty, Sean P. ;

Reyes, Jaime M. ;

Rahl, Peter B. ;

Lin, Charles Y. ;

Sheng, Quanhu ;

Duan, Qiong ;

Federation, Alexander J. ;

Kung, Andrew L. ;

Haldar, Saptarsi M. ;

Young, Richard A. ;

Plutzky, Jorge ;

Bradner, James E. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2018, 115 (09) :2144-2149

[9] Systematic comparison of monoclonal versus polyclonal antibodies for mapping histone modifications by ChIP-seq [J].

Busby, Michele ;

Xue, Catherine ;

Li, Catherine ;

Farjoun, Yossi ;

Gienger, Elizabeth ;

Yofe, Ido ;

Gladden, Adrianne ;

Epstein, Charles B. ;

Cornett, Evan M. ;

Rothbart, Scott B. ;

Nusbaum, Chad ;

Goren, Alon .

EPIGENETICS & CHROMATIN, 2016, 9 :1-16

[10] Inhibition of RNA Polymerase I as a Therapeutic Strategy to Promote Cancer-Specific Activation of p53 [J].

Bywater, Megan J. ;

Poortinga, Gretchen ;

Sanij, Elaine ;

Hein, Nadine ;

Peck, Abigail ;

Cullinane, Carleen ;

Wall, Meaghan ;

Cluse, Leonie ;

Drygin, Denis ;

Anderes, Kenna ;

Huser, Nanni ;

Proffitt, Chris ;

Bliesath, Joshua ;

Haddach, Mustapha ;

Schwaebe, Michael K. ;

Ryckman, David M. ;

Rice, William G. ;

Schmitt, Clemens ;

Lowe, Scott W. ;

Johnstone, Ricky W. ;

Pearson, Richard B. ;

McArthur, Grant A. ;

Hannan, Ross D. .

CANCER CELL, 2012, 22 (01) :51-65

← 1 2 3 4 5 6 7 →