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@ARTICLE{Bandopadhayay:143931,
author = {P. Bandopadhayay and F. Piccioni and R. O'Rourke and P. Ho
and E. M. Gonzalez and G. Buchan and K. Qian and G. Gionet
and E. Girard and M. Coxon and M. G. Rees and L. Brenan and
F. Dubois and O. Shapira and N. F. Greenwald and M. Pages
and A. Balboni Iniguez and B. R. Paolella and A. Meng and C.
Sinai and G. Roti and N. V. Dharia and A. Creech and B.
Tanenbaum and P. Khadka and A. Tracy and H. L. Tiv and A. L.
Hong and S. Coy and R. Rashid and J.-R. Lin and G. S. Cowley
and F. C. Lam and A. Goodale and Y. Lee and K. Schoolcraft
and F. Vazquez and W. C. Hahn and A. Tsherniak and J. E.
Bradner and M. B. Yaffe and T. Milde$^*$ and S. M.
Pfister$^*$ and J. Qi and M. Schenone and S. A. Carr and K.
L. Ligon and M. W. Kieran and S. Santagata and J. M. Olson
and P. C. Gokhale and J. D. Jaffe and D. E. Root and K.
Stegmaier and C. M. Johannessen and R. Beroukhim},
title = {{N}euronal differentiation and cell-cycle programs mediate
response to {BET}-bromodomain inhibition in {MYC}-driven
medulloblastoma.},
journal = {Nature Communications},
volume = {10},
number = {1},
issn = {2041-1723},
address = {[London]},
publisher = {Nature Publishing Group UK},
reportid = {DKFZ-2019-01489},
pages = {2400},
year = {2019},
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.},
cin = {B310 / B062 / L101},
ddc = {500},
cid = {I:(DE-He78)B310-20160331 / I:(DE-He78)B062-20160331 /
I:(DE-He78)L101-20160331},
pnm = {312 - Functional and structural genomics (POF3-312)},
pid = {G:(DE-HGF)POF3-312},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:31160565},
doi = {10.1038/s41467-019-10307-9},
url = {https://inrepo02.dkfz.de/record/143931},
}