TY  - JOUR
AU  - Bandopadhayay, Pratiti
AU  - Piccioni, Federica
AU  - O'Rourke, Ryan
AU  - Ho, Patricia
AU  - Gonzalez, Elizabeth M
AU  - Buchan, Graham
AU  - Qian, Kenin
AU  - Gionet, Gabrielle
AU  - Girard, Emily
AU  - Coxon, Margo
AU  - Rees, Matthew G
AU  - Brenan, Lisa
AU  - Dubois, Frank
AU  - Shapira, Ofer
AU  - Greenwald, Noah F
AU  - Pages, Melanie
AU  - Balboni Iniguez, Amanda
AU  - Paolella, Brenton R
AU  - Meng, Alice
AU  - Sinai, Claire
AU  - Roti, Giovanni
AU  - Dharia, Neekesh V
AU  - Creech, Amanda
AU  - Tanenbaum, Benjamin
AU  - Khadka, Prasidda
AU  - Tracy, Adam
AU  - Tiv, Hong L
AU  - Hong, Andrew L
AU  - Coy, Shannon
AU  - Rashid, Rumana
AU  - Lin, Jia-Ren
AU  - Cowley, Glenn S
AU  - Lam, Fred C
AU  - Goodale, Amy
AU  - Lee, Yenarae
AU  - Schoolcraft, Kathleen
AU  - Vazquez, Francisca
AU  - Hahn, William C
AU  - Tsherniak, Aviad
AU  - Bradner, James E
AU  - Yaffe, Michael B
AU  - Milde, Till
AU  - Pfister, Stefan M
AU  - Qi, Jun
AU  - Schenone, Monica
AU  - Carr, Steven A
AU  - Ligon, Keith L
AU  - Kieran, Mark W
AU  - Santagata, Sandro
AU  - Olson, James M
AU  - Gokhale, Prafulla C
AU  - Jaffe, Jacob D
AU  - Root, David E
AU  - Stegmaier, Kimberly
AU  - Johannessen, Cory M
AU  - Beroukhim, Rameen
TI  - Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma.
JO  - Nature Communications
VL  - 10
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DKFZ-2019-01489
SP  - 2400
PY  - 2019
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:31160565
DO  - DOI:10.1038/s41467-019-10307-9
UR  - https://inrepo02.dkfz.de/record/143931
ER  -