dc.contributor.author | Bandopadhayay, Pratiti | |
dc.contributor.author | Piccioni, Federica | |
dc.contributor.author | O’Rourke, Ryan | |
dc.contributor.author | Ho, Patricia | |
dc.contributor.author | Gonzalez, Elizabeth M. | |
dc.contributor.author | Buchan, Graham | |
dc.contributor.author | Qian, Kenin | |
dc.contributor.author | Gionet, Gabrielle | |
dc.contributor.author | Girard, Emily | |
dc.contributor.author | Coxon, Margo | |
dc.contributor.author | Rees, Matthew G. | |
dc.contributor.author | Brenan, Lisa | |
dc.contributor.author | Dubois, Frank | |
dc.contributor.author | Shapira, Ofer | |
dc.contributor.author | Greenwald, Noah F. | |
dc.contributor.author | Pages, Melanie | |
dc.contributor.author | Balboni Iniguez, Amanda | |
dc.contributor.author | Paolella, Brenton R. | |
dc.contributor.author | Meng, Alice | |
dc.contributor.author | Sinai, Claire | |
dc.contributor.author | Roti, Giovanni | |
dc.contributor.author | Dharia, Neekesh V. | |
dc.contributor.author | Creech, Amanda | |
dc.contributor.author | Tanenbaum, Benjamin | |
dc.contributor.author | Khadka, Prasidda | |
dc.contributor.author | Tracy, Adam | |
dc.contributor.author | Tiv, Hong L. | |
dc.contributor.author | Hong, Andrew L. | |
dc.contributor.author | Coy, Shannon | |
dc.contributor.author | Rashid, Rumana | |
dc.contributor.author | Lin, Jia-Ren | |
dc.contributor.author | Cowley, Glenn S. | |
dc.contributor.author | Lam, Fred Chiu-Lai | |
dc.contributor.author | Goodale, Amy | |
dc.contributor.author | Lee, Yenarae | |
dc.contributor.author | Schoolcraft, Kathleen | |
dc.contributor.author | Vazquez, Francisca | |
dc.contributor.author | Hahn, William C. | |
dc.contributor.author | Tsherniak, Aviad | |
dc.contributor.author | Bradner, James E. | |
dc.contributor.author | Yaffe, Michael B | |
dc.contributor.author | Milde, Till | |
dc.contributor.author | Pfister, Stefan M. | |
dc.contributor.author | Qi, Jun | |
dc.contributor.author | Schenone, Monica | |
dc.contributor.author | Carr, Steven A. | |
dc.contributor.author | Ligon, Keith L. | |
dc.contributor.author | Kieran, Mark W. | |
dc.contributor.author | Santagata, Sandro | |
dc.contributor.author | Olson, James M. | |
dc.contributor.author | Gokhale, Prafulla C. | |
dc.contributor.author | Jaffe, Jacob D. | |
dc.contributor.author | Root, David E. | |
dc.contributor.author | Stegmaier, Kimberly | |
dc.contributor.author | Johannessen, Cory M. | |
dc.contributor.author | Beroukhim, Rameen | |
dc.date.accessioned | 2020-05-21T15:17:55Z | |
dc.date.available | 2020-05-21T15:17:55Z | |
dc.date.issued | 2019-06 | |
dc.date.submitted | 2018-10 | |
dc.identifier.issn | 2041-1723 | |
dc.identifier.uri | https://hdl.handle.net/1721.1/125375 | |
dc.description.abstract | 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. | en_US |
dc.language.iso | en | |
dc.publisher | Springer Science and Business Media LLC | en_US |
dc.relation.isversionof | http://dx.doi.org/10.1038/s41467-019-10307-9 | en_US |
dc.rights | Creative Commons Attribution 4.0 International license | en_US |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | en_US |
dc.source | Nature | en_US |
dc.title | Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma | en_US |
dc.type | Article | en_US |
dc.identifier.citation | Bandopadhayay, P. et al. "Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma." Nature Communications 10, 1 (June 2019): 2400 © 2019 The Author(s) | en_US |
dc.contributor.department | Koch Institute for Integrative Cancer Research at MIT | en_US |
dc.relation.journal | Nature Communications | en_US |
dc.eprint.version | Final published version | en_US |
dc.type.uri | http://purl.org/eprint/type/JournalArticle | en_US |
eprint.status | http://purl.org/eprint/status/PeerReviewed | en_US |
dc.date.updated | 2020-02-04T16:02:35Z | |
dspace.date.submission | 2020-02-04T16:02:38Z | |
mit.journal.volume | 10 | en_US |
mit.journal.issue | 1 | en_US |
mit.license | PUBLISHER_CC | |
mit.metadata.status | Complete | |