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

Author

Listed:
  • Pratiti Bandopadhayay

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
    Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Federica Piccioni

    (Broad Institute of MIT and Harvard)

  • Ryan O’Rourke

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
    Broad Institute of MIT and Harvard)

  • Patricia Ho

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
    Broad Institute of MIT and Harvard)

  • Elizabeth M. Gonzalez

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
    Broad Institute of MIT and Harvard)

  • Graham Buchan

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
    Broad Institute of MIT and Harvard)

  • Kenin Qian

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
    Broad Institute of MIT and Harvard)

  • Gabrielle Gionet

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
    Broad Institute of MIT and Harvard)

  • Emily Girard

    (Fred Hutchinson Cancer Research Center)

  • Margo Coxon

    (Fred Hutchinson Cancer Research Center)

  • Matthew G. Rees

    (Broad Institute of MIT and Harvard)

  • Lisa Brenan

    (Broad Institute of MIT and Harvard)

  • Frank Dubois

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute)

  • Ofer Shapira

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute)

  • Noah F. Greenwald

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Brigham and Women’s Hospital)

  • Melanie Pages

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
    Broad Institute of MIT and Harvard)

  • Amanda Balboni Iniguez

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
    Broad Institute of MIT and Harvard)

  • Brenton R. Paolella

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute)

  • Alice Meng

    (Dana-Farber Cancer Institute)

  • Claire Sinai

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
    Dana-Farber Cancer Institute)

  • Giovanni Roti

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
    Broad Institute of MIT and Harvard
    University of Parma)

  • Neekesh V. Dharia

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
    Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Amanda Creech

    (Broad Institute of MIT and Harvard)

  • Benjamin Tanenbaum

    (Broad Institute of MIT and Harvard)

  • Prasidda Khadka

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
    Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Adam Tracy

    (Broad Institute of MIT and Harvard)

  • Hong L. Tiv

    (Experimental Therapeutics Core and Belfer Center for Applied Cancer Science)

  • Andrew L. Hong

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
    Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Shannon Coy

    (Brigham and Women’s Hospital)

  • Rumana Rashid

    (Brigham and Women’s Hospital
    Harvard Medical School)

  • Jia-Ren Lin

    (Harvard Medical School
    Harvard Medical School)

  • Glenn S. Cowley

    (Broad Institute of MIT and Harvard
    Janssen Research and Development (Johnson & Johnson))

  • Fred C. Lam

    (Koch Institute for Integrative Cancer Research, MIT)

  • Amy Goodale

    (Broad Institute of MIT and Harvard)

  • Yenarae Lee

    (Broad Institute of MIT and Harvard)

  • Kathleen Schoolcraft

    (Dana-Farber Cancer Institute)

  • Francisca Vazquez

    (Broad Institute of MIT and Harvard)

  • William C. Hahn

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School)

  • Aviad Tsherniak

    (Broad Institute of MIT and Harvard)

  • James E. Bradner

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute
    Harvard Medical School
    Novartis Institutes for Biomedical Research)

  • Michael B. Yaffe

    (Broad Institute of MIT and Harvard
    Koch Institute for Integrative Cancer Research, MIT)

  • Till Milde

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    CCU Pediatric Oncology, German Cancer Research Center (DKFZ)
    Heidelberg University Hospital)

  • Stefan M. Pfister

    (Hopp Children’s Cancer Center Heidelberg (KiTZ)
    German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ)
    Heidelberg University Hospital)

  • Jun Qi

    (Dana-Farber Cancer Institute)

  • Monica Schenone

    (Broad Institute of MIT and Harvard)

  • Steven A. Carr

    (Broad Institute of MIT and Harvard)

  • Keith L. Ligon

    (Broad Institute of MIT and Harvard
    Brigham and Women’s Hospital
    Harvard Medical School
    Dana-Farber Cancer Institute)

  • Mark W. Kieran

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
    Harvard Medical School)

  • Sandro Santagata

    (Dana-Farber Cancer Institute
    Brigham and Women’s Hospital)

  • James M. Olson

    (Fred Hutchinson Cancer Research Center)

  • Prafulla C. Gokhale

    (Experimental Therapeutics Core and Belfer Center for Applied Cancer Science)

  • Jacob D. Jaffe

    (Broad Institute of MIT and Harvard)

  • David E. Root

    (Broad Institute of MIT and Harvard)

  • Kimberly Stegmaier

    (Dana-Farber/Boston Children’s Cancer and Blood Disorders Center
    Broad Institute of MIT and Harvard
    Harvard Medical School)

  • Cory M. Johannessen

    (Broad Institute of MIT and Harvard)

  • Rameen Beroukhim

    (Broad Institute of MIT and Harvard
    Fred Hutchinson Cancer Research Center
    Dana-Farber Cancer Institute
    Harvard Medical School)

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.

Suggested Citation

  • Pratiti Bandopadhayay & Federica Piccioni & Ryan O’Rourke & Patricia Ho & Elizabeth M. Gonzalez & Graham Buchan & Kenin Qian & Gabrielle Gionet & Emily Girard & Margo Coxon & Matthew G. Rees & Lisa Br, 2019. "Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10307-9
    DOI: 10.1038/s41467-019-10307-9
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    Cited by:

    1. Noha A. M. Shendy & Melissa Bikowitz & Logan H. Sigua & Yang Zhang & Audrey Mercier & Yousef Khashana & Stephanie Nance & Qi Liu & Ian M. Delahunty & Sarah Robinson & Vanshita Goel & Matthew G. Rees &, 2024. "Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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