%0 Journal Article
%A Bandopadhayay, Pratiti
%A Piccioni, Federica
%A O'Rourke, Ryan
%A Ho, Patricia
%A Gonzalez, Elizabeth M
%A Buchan, Graham
%A Qian, Kenin
%A Gionet, Gabrielle
%A Girard, Emily
%A Coxon, Margo
%A Rees, Matthew G
%A Brenan, Lisa
%A Dubois, Frank
%A Shapira, Ofer
%A Greenwald, Noah F
%A Pages, Melanie
%A Balboni Iniguez, Amanda
%A Paolella, Brenton R
%A Meng, Alice
%A Sinai, Claire
%A Roti, Giovanni
%A Dharia, Neekesh V
%A Creech, Amanda
%A Tanenbaum, Benjamin
%A Khadka, Prasidda
%A Tracy, Adam
%A Tiv, Hong L
%A Hong, Andrew L
%A Coy, Shannon
%A Rashid, Rumana
%A Lin, Jia-Ren
%A Cowley, Glenn S
%A Lam, Fred C
%A Goodale, Amy
%A Lee, Yenarae
%A Schoolcraft, Kathleen
%A Vazquez, Francisca
%A Hahn, William C
%A Tsherniak, Aviad
%A Bradner, James E
%A Yaffe, Michael B
%A Milde, Till
%A Pfister, Stefan M
%A Qi, Jun
%A Schenone, Monica
%A Carr, Steven A
%A Ligon, Keith L
%A Kieran, Mark W
%A Santagata, Sandro
%A Olson, James M
%A Gokhale, Prafulla C
%A Jaffe, Jacob D
%A Root, David E
%A Stegmaier, Kimberly
%A Johannessen, Cory M
%A Beroukhim, Rameen
%T Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma.
%J Nature Communications
%V 10
%N 1
%@ 2041-1723
%C [London]
%I Nature Publishing Group UK
%M DKFZ-2019-01489
%P 2400
%D 2019
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:31160565
%R 10.1038/s41467-019-10307-9
%U https://inrepo02.dkfz.de/record/143931