ArticleNature communications2019
Neuronal differentiation and cell-cycle programs mediate response to BET-bromodomain inhibition in MYC-driven medulloblastoma.
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Article in Nature communications, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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38citing papers in PubMed
3.9field-weighted citation impact, top 6% of its field
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Who cites it
38 citing papers in PubMed, 60 citations in OpenAlex.
- Divergent medulloblastoma chromatin states disclose KDM2B as a selective dependency.Nature genetics · 2026Article
- From developmental origins to relapse: molecular and therapeutic insights in medulloblastoma.Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery · 2026Review
- Targeting TET3 suppresses group 3 medulloblastoma stemness and progression via impairing hypomethylation of Otx2 super-enhancer.Cell reports. Medicine · 2025Article
- Targeting processive transcription for Myc-driven circuitry in medulloblastoma.Neuro-oncology · 2025Article
- Recurrent breakpoints in the BRD4 locus reduce toxicity associated with gene amplification.Cell genomics · 2025Article
- Targeting BRD4 to attenuate RANKL-induced osteoclast activation and bone erosion in rheumatoid arthritis.Molecular and cellular biochemistry · 2025Article
- A compendium of Amplification-Related Gain Of Sensitivity genes in human cancer.Nature communications · 2025Article
- Targeting protein synthesis pathways in MYC-amplified medulloblastoma.Discover oncology · 2025Review
- Mechanistic insights into medulloblastoma relapse.Pharmacology & therapeutics · 2024Review
- Drivers Underlying Metastasis and Relapse in Medulloblastoma and Targeting Strategies.Cancers · 2024Review
- Group 3 medulloblastoma transcriptional networks collapse under domain specific EP300/CBP inhibition.Nature communications · 2024Article
- Targeting TRIP13 in favorable histology Wilms tumor with nuclear export inhibitors synergizes with doxorubicin.Communications biology · 2024Article
- A therapeutically targetable positive feedback loop between lnc-HLX-2-7, HLX, and MYC that promotes group 3 medulloblastoma.Cell reports · 2024Article
- Recent progress and structural analyses of domain-selective BET inhibitors.Medicinal research reviews · 2023Review
- Genome-wide pooled CRISPR screening in neurospheres.Nature protocols · 2023Review
- DNA-PKcs as an upstream mediator of OCT4-induced MYC activation in small cell lung cancer.Biochimica et biophysica acta. Gene regulatory mechanisms · 2023Article
- Bromodomain and Extraterminal Domain (BET) Protein Inhibition Hinders Glioblastoma Progression by Inducing Autophagy-Dependent Differentiation.International journal of molecular sciences · 2023Article
- Metabolic rewiring in MYC-driven medulloblastoma by BET-bromodomain inhibition.Scientific reports · 2023Article
- Combination of Ribociclib with BET-Bromodomain and PI3K/mTOR Inhibitors for Medulloblastoma Treatment In Vitro and In Vivo.Molecular cancer therapeutics · 2023Article
- Super enhancers: Pathogenic roles and potential therapeutic targets for acute myeloid leukemia (AML).Genes & diseases · 2022Review
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Authors and funding
56 authors at 8 institutions in 5 countries.
Pratiti BandopadhayayDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.
Federica PiccioniBroad Institute of MIT and Harvard, Cambridge, USA.ORCID http://orcid.org/0000-0003-1210-3210
Ryan O'RourkeDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.
Patricia HoDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.
Elizabeth M GonzalezDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.
Graham BuchanDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.
Kenin QianDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.
Gabrielle GionetDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.
Emily GirardClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, USA.
Margo CoxonClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, USA.
Matthew G ReesBroad Institute of MIT and Harvard, Cambridge, USA.ORCID http://orcid.org/0000-0002-2987-7581
Lisa BrenanBroad Institute of MIT and Harvard, Cambridge, USA.
Frank DuboisBroad Institute of MIT and Harvard, Cambridge, USA.
Ofer ShapiraBroad Institute of MIT and Harvard, Cambridge, USA.
Noah F GreenwaldBroad Institute of MIT and Harvard, Cambridge, USA.ORCID http://orcid.org/0000-0002-7836-4379
Melanie PagesDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.
Amanda Balboni IniguezDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.
Brenton R PaolellaBroad Institute of MIT and Harvard, Cambridge, USA.
Alice MengDivision of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA.
Claire SinaiDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.
Giovanni RotiDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.
Neekesh V DhariaDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.ORCID http://orcid.org/0000-0001-5048-067X
Amanda CreechBroad Institute of MIT and Harvard, Cambridge, USA.
Benjamin TanenbaumBroad Institute of MIT and Harvard, Cambridge, USA.
Prasidda KhadkaDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.
Adam TracyBroad Institute of MIT and Harvard, Cambridge, USA.
Hong L TivExperimental Therapeutics Core and Belfer Center for Applied Cancer Science, Boston, USA.ORCID http://orcid.org/0000-0002-5628-3965
Andrew L HongDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.ORCID http://orcid.org/0000-0003-0374-1667
Shannon CoyDepartment of Pathology, Brigham and Women's Hospital, Boston, USA.
Rumana RashidDepartment of Pathology, Brigham and Women's Hospital, Boston, USA.
Jia-Ren LinLaboratory of Systems Pharmacology, Harvard Medical School, Boston, USA.ORCID http://orcid.org/0000-0003-4702-7705
Glenn S CowleyBroad Institute of MIT and Harvard, Cambridge, USA.ORCID http://orcid.org/0000-0002-0526-0616
Fred C LamKoch Institute for Integrative Cancer Research, MIT, Cambridge, USA.
Amy GoodaleBroad Institute of MIT and Harvard, Cambridge, USA.
Yenarae LeeBroad Institute of MIT and Harvard, Cambridge, USA.
Kathleen SchoolcraftDivision of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA.
Francisca VazquezBroad Institute of MIT and Harvard, Cambridge, USA.ORCID http://orcid.org/0000-0002-2857-4685
William C HahnBroad Institute of MIT and Harvard, Cambridge, USA.ORCID http://orcid.org/0000-0003-2840-9791
Aviad TsherniakBroad Institute of MIT and Harvard, Cambridge, USA.ORCID http://orcid.org/0000-0002-3797-1877
James E BradnerBroad Institute of MIT and Harvard, Cambridge, USA.ORCID http://orcid.org/0000-0002-2718-4415
Michael B YaffeBroad Institute of MIT and Harvard, Cambridge, USA.
Till MildeHopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
Stefan M PfisterHopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
Jun QiDivision of Cancer Biology, Dana-Farber Cancer Institute, Boston, USA.
Monica SchenoneBroad Institute of MIT and Harvard, Cambridge, USA.ORCID http://orcid.org/0000-0002-6456-8768
Steven A CarrBroad Institute of MIT and Harvard, Cambridge, USA.
Keith L LigonBroad Institute of MIT and Harvard, Cambridge, USA.
Mark W KieranDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.
Sandro SantagataDivision of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA.ORCID http://orcid.org/0000-0002-7528-9668
James M OlsonClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, USA.
Prafulla C GokhaleExperimental Therapeutics Core and Belfer Center for Applied Cancer Science, Boston, USA.
Jacob D JaffeBroad Institute of MIT and Harvard, Cambridge, USA.ORCID http://orcid.org/0000-0001-9845-1210
David E RootBroad Institute of MIT and Harvard, Cambridge, USA.ORCID http://orcid.org/0000-0001-5122-861X
Kimberly StegmaierDana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, USA.
Cory M JohannessenBroad Institute of MIT and Harvard, Cambridge, USA. cory.johannessen@gmail.com.
Rameen BeroukhimBroad Institute of MIT and Harvard, Cambridge, USA. Rameen_Beroukhim@dfci.harvard.edu.ORCID http://orcid.org/0000-0001-6303-3609
Broad Institute · USDana-Farber Cancer Institute · USBrigham and Women's Hospital · USFred Hutch Cancer Center · USGerman Cancer Research Center · DEHarvard University · USAllen Institute · USDana-Farber/Boston Children's Cancer and Blood Disorders Center · US
Funding
TOXICOLOGY CORE UNITP30ES002109 · NIEHS · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI FOX, JAMES G · 1985 to 2020
$25.6MSystems Pharmacology of Therapeutic and Adverse Responses to ImmuneCheckpoint and Small Molecule DrugsU54CA225088 · NCI · HARVARD MEDICAL SCHOOL · PI SORGER, PETER KARL · 2018 to 2022
$10.8MThe Dana-Farber Cancer Institute Cancer Target Discovery and Development CenterU01CA176058 · NCI · DANA-FARBER CANCER INST · PI HAHN, WILLIAM C. · 2013 to 2021
$7.8MIntegrating Transforming Approaches to Identify and Target New Vulnerabilities in CancerR35CA210030 · NCI · DANA-FARBER CANCER INST · PI STEGMAIER, KIMBERLY · 2016 to 2022
$7.3MGenetic evolution of glioblastomas during radiation and temozolomide therapyR01CA188228 · NCI · DANA-FARBER CANCER INST · PI BEROUKHIM, RAMEEN, CHAKRAVARTI, ARNAB · 2015 to 2025
$6.9MProject 2U54CA224068 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI CORCORAN, RYAN BRUCE, FLAHERTY, KEITH T · 2017 to 2021
$6.3MTesting a cancer patient-specific SARS-CoV-2 vaccine in chemotherapy- and radiation-treated pediatric brain tumor mouse modelsR01CA114567 · NCI · SEATTLE CHILDREN'S HOSPITAL · PI OLSON, JAMES M · 2006 to 2023
$4.9MTargeting BET-bromodomains in neuroblastomaR01NS088355 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI STEGMAIER, KIMBERLY, WEISS, WILLIAM A · 2015 to 2019
$3.3MCharacterizing TP53 and PPM1D mutations as resistance drivers to radiation therapy in Diffuse Intrinsic Pontine GliomasR01CA219943 · NCI · BROAD INSTITUTE, INC. · PI BEROUKHIM, RAMEEN, LIGON, KEITH LLOYD · 2017 to 2021
$2.5MCharacterizing the resistance mechanisms to BET-bromodomain inhibition in MYC-amplified medulloblastomaR00CA201592 · NCI · DANA-FARBER CANCER INST · PI BANDOPADHAYAY, PRATITI · 2018 to 2020
$697kCharacterizing the resistance mechanisms to BET-bromodomain inhibition in MYC-amplified medulloblastomaK99CA201592 · NCI · DANA-FARBER CANCER INST · PI BANDOPADHAYAY, PRATITI · 2016 to 2017
$302kCancer Specific Sensitivity to Suppression of Spliceosome ComponentsF32CA180653 · NCI · DANA-FARBER CANCER INST · PI PAOLELLA, BRENTON ROBERT · 2014 to 2017
$148kNCI NIH HHS F32 CA180653NCI NIH HHS K99 CA201592NCI NIH HHS R00 CA201592NCI NIH HHS R01 CA114567NCI NIH HHS R01 CA188228NCI NIH HHS R01 CA219943NCI NIH HHS R35 CA210030NCI NIH HHS U01 CA176058NCI NIH HHS U54 CA224068NCI NIH HHS U54 CA225088NIEHS NIH HHS P30 ES002109NINDS NIH HHS R01 NS088355
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.
Indexed as
AnimalsAzepinesBasic Helix-Loop-Helix ProteinsBromodomain Containing ProteinsCell CycleCell Cycle ProteinsCell LineageCell Line, TumorCerebellar NeoplasmsCRISPR-Cas SystemsCyclin D2Cyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6Drug Resistance, NeoplasmGene Expression ProfilingHumansAzepinesBasic Helix-Loop-Helix Proteinsbromodomain and extra-terminal domain protein, humanBromodomain Containing ProteinsCell Cycle ProteinsCyclin D2Cyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6(+)-JQ1 compoundMYC protein, humanProteinsProto-Oncogene Proteins c-mycTriazoles
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