Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma Academic Article uri icon

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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.

authors

  • Bandopadhayay, Pratiti
  • Piccioni, Federica
  • O’Rourke, Ryan
  • Ho, Patricia
  • Gonzalez, Elizabeth M
  • Buchan, Graham
  • Qian, Kenin
  • Gionet, Gabrielle
  • Girard, Emily
  • Coxon, Margo
  • Rees, Matthew G
  • Brenan, Lisa
  • Dubois, Frank
  • Shapira, Ofer
  • Greenwald, Noah F
  • Pages, Melanie
  • Balboni Iniguez, Amanda
  • Paolella, Brenton R
  • Meng, Alice
  • Sinai, Claire
  • Roti, Giovanni
  • Dharia, Neekesh V
  • Creech, Amanda
  • Tanenbaum, Benjamin
  • Khadka, Prasidda
  • Tracy, Adam
  • Tiv, Hong L
  • Hong, Andrew L
  • Coy, Shannon
  • Rashid, Rumana
  • Lin, Jia-Ren
  • Cowley, Glenn S
  • Lam, Fred
  • Goodale, Amy
  • Lee, Yenarae
  • Schoolcraft, Kathleen
  • Vazquez, Francisca
  • Hahn, William C
  • Tsherniak, Aviad
  • Bradner, James E
  • Yaffe, Michael B
  • Milde, Till
  • Pfister, Stefan M
  • Qi, Jun
  • Schenone, Monica
  • Carr, Steven A
  • Ligon, Keith L
  • Kieran, Mark W
  • Santagata, Sandro
  • Olson, James M
  • Gokhale, Prafulla C
  • Jaffe, Jacob D
  • Root, David E
  • Stegmaier, Kimberly
  • Johannessen, Cory M
  • Beroukhim, Rameen

publication date

  • December 2019

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