Journal Article

DKFZ-2019-01489

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma.

Bandopadhayay, P. ; Piccioni, F. ; O'Rourke, R. ; Ho, P. ; Gonzalez, E. M. ; Buchan, G. ; Qian, K. ; Gionet, G. ; Girard, E. ; Coxon, M. ; Rees, M. G. ; Brenan, L. ; Dubois, F. ; Shapira, O. ; Greenwald, N. F. ; Pages, M. ; Balboni Iniguez, A. ; Paolella, B. R. ; Meng, A. ; Sinai, C. ; Roti, G. ; Dharia, N. V. ; Creech, A. ; Tanenbaum, B. ; Khadka, P. ; Tracy, A. ; Tiv, H. L. ; Hong, A. L. ; Coy, S. ; Rashid, R. ; Lin, J.-R. ; Cowley, G. S. ; Lam, F. C. ; Goodale, A. ; Lee, Y. ; Schoolcraft, K. ; Vazquez, F. ; Hahn, W. C. ; Tsherniak, A. ; Bradner, J. E. ; Yaffe, M. B. ; Milde, T.DKFZ* ; Pfister, S. M.DKFZ* ; Qi, J. ; Schenone, M. ; Carr, S. A. ; Ligon, K. L. ; Kieran, M. W. ; Santagata, S. ; Olson, J. M. ; Gokhale, P. C. ; Jaffe, J. D. ; Root, D. E. ; Stegmaier, K. ; Johannessen, C. M. ; Beroukhim, R.

2019
Nature Publishing Group UK [London]

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Please use a persistent id in citations: doi:10.1038/s41467-019-10307-9

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.

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Contributing Institute(s):

1. KKE Pädiatrische Onkologie (B310)
2. Pädiatrische Neuroonkologie (B062)
3. DKTK Heidelberg (L101)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2019

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