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000143931 1001_ $$aBandopadhayay, Pratiti$$b0
000143931 245__ $$aNeuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma.
000143931 260__ $$a[London]$$bNature Publishing Group UK$$c2019
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000143931 520__ $$aBET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms for its action, and ultimately for resistance, have not been fully defined. Here, using a combination of expression profiling, genome-scale CRISPR/Cas9-mediated loss of function and ORF/cDNA driven rescue screens, and cell-based models of spontaneous resistance, we identify bHLH/homeobox transcription factors and cell-cycle regulators as key genes mediating BETi's response and resistance. Cells that acquire drug tolerance exhibit a more neuronally differentiated cell-state and expression of lineage-specific bHLH/homeobox transcription factors. However, they do not terminally differentiate, maintain expression of CCND2, and continue to cycle through S-phase. Moreover, CDK4/CDK6 inhibition delays acquisition of resistance. Therefore, our data provide insights about the mechanisms underlying BETi effects and the appearance of resistance and support the therapeutic use of combined cell-cycle inhibitors with BETi in MYC-amplified medulloblastoma.
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000143931 7001_ $$00000-0003-1210-3210$$aPiccioni, Federica$$b1
000143931 7001_ $$aO'Rourke, Ryan$$b2
000143931 7001_ $$aHo, Patricia$$b3
000143931 7001_ $$aGonzalez, Elizabeth M$$b4
000143931 7001_ $$aBuchan, Graham$$b5
000143931 7001_ $$aQian, Kenin$$b6
000143931 7001_ $$aGionet, Gabrielle$$b7
000143931 7001_ $$aGirard, Emily$$b8
000143931 7001_ $$aCoxon, Margo$$b9
000143931 7001_ $$00000-0002-2987-7581$$aRees, Matthew G$$b10
000143931 7001_ $$aBrenan, Lisa$$b11
000143931 7001_ $$aDubois, Frank$$b12
000143931 7001_ $$aShapira, Ofer$$b13
000143931 7001_ $$00000-0002-7836-4379$$aGreenwald, Noah F$$b14
000143931 7001_ $$aPages, Melanie$$b15
000143931 7001_ $$aBalboni Iniguez, Amanda$$b16
000143931 7001_ $$aPaolella, Brenton R$$b17
000143931 7001_ $$aMeng, Alice$$b18
000143931 7001_ $$aSinai, Claire$$b19
000143931 7001_ $$aRoti, Giovanni$$b20
000143931 7001_ $$00000-0001-5048-067X$$aDharia, Neekesh V$$b21
000143931 7001_ $$aCreech, Amanda$$b22
000143931 7001_ $$aTanenbaum, Benjamin$$b23
000143931 7001_ $$aKhadka, Prasidda$$b24
000143931 7001_ $$aTracy, Adam$$b25
000143931 7001_ $$00000-0002-5628-3965$$aTiv, Hong L$$b26
000143931 7001_ $$00000-0003-0374-1667$$aHong, Andrew L$$b27
000143931 7001_ $$aCoy, Shannon$$b28
000143931 7001_ $$aRashid, Rumana$$b29
000143931 7001_ $$00000-0003-4702-7705$$aLin, Jia-Ren$$b30
000143931 7001_ $$00000-0002-0526-0616$$aCowley, Glenn S$$b31
000143931 7001_ $$aLam, Fred C$$b32
000143931 7001_ $$aGoodale, Amy$$b33
000143931 7001_ $$aLee, Yenarae$$b34
000143931 7001_ $$aSchoolcraft, Kathleen$$b35
000143931 7001_ $$00000-0002-2857-4685$$aVazquez, Francisca$$b36
000143931 7001_ $$00000-0003-2840-9791$$aHahn, William C$$b37
000143931 7001_ $$00000-0002-3797-1877$$aTsherniak, Aviad$$b38
000143931 7001_ $$00000-0002-2718-4415$$aBradner, James E$$b39
000143931 7001_ $$aYaffe, Michael B$$b40
000143931 7001_ $$0P:(DE-He78)0be2f86573954f87e97f8a4dbb05cb0f$$aMilde, Till$$b41$$udkfz
000143931 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan M$$b42$$udkfz
000143931 7001_ $$aQi, Jun$$b43
000143931 7001_ $$00000-0002-6456-8768$$aSchenone, Monica$$b44
000143931 7001_ $$aCarr, Steven A$$b45
000143931 7001_ $$aLigon, Keith L$$b46
000143931 7001_ $$aKieran, Mark W$$b47
000143931 7001_ $$00000-0002-7528-9668$$aSantagata, Sandro$$b48
000143931 7001_ $$aOlson, James M$$b49
000143931 7001_ $$aGokhale, Prafulla C$$b50
000143931 7001_ $$00000-0001-9845-1210$$aJaffe, Jacob D$$b51
000143931 7001_ $$00000-0001-5122-861X$$aRoot, David E$$b52
000143931 7001_ $$aStegmaier, Kimberly$$b53
000143931 7001_ $$aJohannessen, Cory M$$b54
000143931 7001_ $$00000-0001-6303-3609$$aBeroukhim, Rameen$$b55
000143931 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-019-10307-9$$gVol. 10, no. 1, p. 2400$$n1$$p2400$$tNature Communications$$v10$$x2041-1723$$y2019
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