2. Academic Validation
  3. Transcription Elongation Machinery Is a Druggable Dependency and Potentiates Immunotherapy in Glioblastoma Stem Cells

Transcription Elongation Machinery Is a Druggable Dependency and Potentiates Immunotherapy in Glioblastoma Stem Cells

  • Cancer Discov. 2022 Feb;12(2):502-521. doi: 10.1158/2159-8290.CD-20-1848.
Zhixin Qiu  # 1 2,  Linjie Zhao  # 1 2,  Jia Z Shen  # 3,  Zhengyu Liang 4,  Qiulian Wu 1 2,  Kailin Yang 5,  Lihua Min 1,  Ryan C Gimple 2 6,  Qiyuan Yang 7,  Shruti Bhargava 2,  Chunyu Jin 8,  Cheryl Kim 9,  Denise Hinz 9,  Deobrat Dixit 2,  Jean A Bernatchez 10,  Briana C Prager 2 6,  Guoxin Zhang 2,  Zhen Dong 2,  Deguan Lv 1 2,  Xujun Wang 11,  Leo J Y Kim 2 6,  Zhe Zhu 2,  Katherine A Jones 12,  Ye Zheng 7,  Xiuxing Wang 2 13,  Jair L Siqueira-Neto 10,  Lukas Chavez 14,  Xiang-Dong Fu 4,  Charles Spruck 15,  Jeremy N Rich 16 2 17 18
Affiliations

Affiliations

  • 1 Hillman Cancer Center and Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
  • 2 Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, California.
  • 3 Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
  • 4 Department of Cellular and Molecular Medicine, Institute of Genomic Medicine, University of California, San Diego, La Jolla, California.
  • 5 Department of Radiation Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, Ohio.
  • 6 Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
  • 7 NOMIS Center for Immunobiology and Microbial Pathogenesis, The Salk Institute for Biological Studies, La Jolla, California.
  • 8 Howard Hughes Medical Institute, Department of Medicine, University of California, San Diego, La Jolla, California.
  • 9 Flow Cytometry Core Facility, La Jolla Institute for Immunology, La Jolla, California.
  • 10 Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California.
  • 11 SJTU-Yale Joint Center for Biostatistics, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
  • 12 Regulatory Biology Laboratory, The Salk Institute for Biological Studies, La Jolla, California.
  • 13 School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 14 Department of Medicine, University of California, San Diego, La Jolla, California.
  • 15 Tumor Initiation and Maintenance Program, NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California. [email protected] [email protected].
  • 16 Hillman Cancer Center and Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. [email protected] [email protected].
  • 17 Sanford Consortium for Regenerative Medicine, La Jolla, California.
  • 18 Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania.
  • # Contributed equally.
PMID: 34615656 DOI: 10.1158/2159-8290.CD-20-1848
Abstract

Glioblastoma (GBM) is the most lethal primary brain Cancer characterized by therapeutic resistance, which is promoted by GBM stem cells (GSC). Here, we interrogated gene expression and whole-genome CRISPR/Cas9 screening in a large panel of patient-derived GSCs, differentiated GBM cells (DGC), and neural stem cells (NSC) to identify master regulators of GSC stemness, revealing an essential transcription state with increased RNA polymerase II-mediated transcription. The YY1 and transcriptional CDK9 complex was essential for GSC survival and maintenance in vitro and in vivo. YY1 interacted with CDK9 to regulate transcription elongation in GSCs. Genetic or pharmacologic targeting of the YY1-CDK9 complex elicited RNA m6A modification-dependent interferon responses, reduced regulatory T-cell infiltration, and augmented efficacy of immune checkpoint therapy in GBM. Collectively, these results suggest that YY1-CDK9 transcription elongation complex defines a targetable cell state with active transcription, suppressed interferon responses, and immunotherapy resistance in GBM. SIGNIFICANCE: Effective strategies to rewire immunosuppressive microenvironment and enhance immunotherapy response are still lacking in GBM. YY1-driven transcriptional elongation machinery represents a druggable target to activate interferon response and enhance anti-PD-1 response through regulating the m6A modification program, linking epigenetic regulation to immunomodulatory function in GBM.This article is highlighted in the In This Issue feature, p. 275.

Figures
Products