Targeting Processive Transcription For Myc-driven Circuitry in Medulloblastoma.

Details

• Alternative Title:
  Neuro-Oncology, 2025, v. 27, no. 10: Targeting Processive Transcription For Myc-driven Circuitry in Medulloblastoma.
• Journal Article:
  Neuro-Oncology
• Personal Author:
  Sobral, Lays Martin ; Walker, Faye M. ; Madhavan, Krishna ; Janko, Elizabeth ; Donthula, Sahiti ; Danis, Etienne ; Bompada, Pradeep ; Balakrishnan, Ilango ; Wang, Dong ; Pierce, Angela ; Haag, Mary M. ; Carstens, Billie J. ; Serkova, Natalie J. ; Foreman, Nicholas K. ; Venkataraman, Sujatha ; Veo, Bethany ; Vibhakar, Rajeev ; Dahl, Nathan A.
• Description:
  Medulloblastoma is the most common malignant brain tumor of childhood. The highest-risk tumors are driven by recurrent Myc amplifications (Myc-MB) and experience poorer outcomes despite intensive multimodal therapy. The Myc transcription factor defines core regulatory circuitry for these tumors and acts to broadly amplify downstream pro-survival transcriptional programs. Therapeutic targeting of Myc directly has proven elusive, but inhibiting transcriptional cofactors may present an indirect means of drugging the oncogenic transcriptional circuitry sustaining Myc-MB.
  
  Independent CRISPR-Cas9 screens were pooled to identify conserved dependencies in Myc-MB. We performed chromatin conformation capture (Hi-C) from primary patient Myc-MB samples to map enhancer-promoter interactions. We then treated in vitro and xenograft models with CDK9/7 inhibitors to evaluate the effect on Myc-driven programs and tumor growth.
  
  Eight CRISPR-Cas9 screens performed across 3 independent labs identify CDK9 as a conserved dependency in Myc-MB. Myc-MB cells are susceptible to CDK9 inhibition, which is synergistic with concurrent inhibition of CDK7. Inhibition of transcriptional CDKs disrupts enhancer-promoter activity in Myc-MB and downregulates Myc-driven transcriptional programs, exerting a potent antitumor effect.
  
  Our findings identify CDK9 inhibition as a translationally promising strategy for the treatment of Myc-MB.
• Content Notes:
  Author manuscript
• Subjects:
  • Medulloblastoma
  • Humans
  • Animals
  • Mice
  • Proto-Oncogene Proteins c-myc
  • Cerebellar Neoplasms
  • CRISPR-Cas Systems
  • Xenograft Model Antitumor Assays
  • Gene Expression Regulation, Neoplastic
  • Transcription, Genetic
  More +
• Keywords:
  • Medulloblastoma
  • Myc
  • CDK7
  • CDK9
  • medulloblastoma
• Source:
  Neuro-Oncology, 2025, v. 27, no. 10
• DOI:
  https://doi.org/10.1093/neuonc/noaf121
• ISSN:
  1522-8517 ; 1523-5866
• Pubmed ID:
  40372972
• Pubmed Central ID:
  PMC12833536
• Document Type:
  Text
• Funding:
  K08 NS121592/NS/NINDS NIH HHSUnited States/ ; P30 CA046934/CA/NCI NIH HHSUnited States/ ; R01 NS091219/NS/NINDS NIH HHSUnited States/ ; S10 OD023485/OD/NIH HHSUnited States/ ; K08NS121592/NS/NINDS NIH HHSUnited States/ ; R01NS091219/NS/NINDS NIH HHSUnited States/ ; MUJP.2021.003/University of Colorado Cancer Center/Molecular, Cellular, and Developmental Biology/ ; P30 CA046934/CA/NCI NIH HHSUnited States/ ; S10 OD023485/CD/ODCDC CDC HHSUnited States/
• Genre:
  Journal Article
• Pages in Document:
  2697-2710 (27 pdf pages)
• Volume:
  27
• Issue:
  10
• Download URL:
  https://stacks.cdc.gov/view/cdc/261407/cdc_261407_DS1.pdf
• File Type:
  [PDF - 2.72 MB]
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:fe256e9c9b97c7e3e0c5b98208cbbb8061f39dd1963eb031ab0bb00752af3eab7f5c8f144f83ee3c1df40abf3c5eecd9a240ff9ce066c191e4e140289e83fcb4