VHL synthetic lethality screens uncover CBF-β as a negative regulator of STING
Clear cell renal cell carcinoma (ccRCC) represents the most common form of kidney cancer and is typified by biallelic inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene. Here, we undertake genome-wide CRISPR/Cas9 screening to reveal synthetic lethal interactors of VHL, and uncover that loss of Core Binding Factor β (CBF-β) causes cell death in VHL-null ccRCC cell lines and impairs tumour establishment and growth in vivo. This synthetic relationship is independent of the elevated activity of hypoxia inducible factors (HIFs) in VHL-null cells, but does involve the RUNX transcription factors that are known binding partners of CBF-β. Mechanistically, CBF-β loss leads to upregulation of type I interferon signalling, and we uncover a direct inhibitory role for CBF-β at the STING locus controlling Interferon Stimulated Gene expression. Targeting CBF-β in kidney cancer both selectively induces tumour cell lethality and promotes activation of type I interferon signalling.
Authors
- James A. Nathan (ORCID: https://orcid.org/0000-0002-0248-1632)
- Tekle Pauzaite (ORCID: https://orcid.org/0000-0002-0668-3661)
- James C. Williamson (ORCID: https://orcid.org/0000-0002-2009-189X)
- Anneliese O. Speak (ORCID: https://orcid.org/0000-0003-4890-4685)
- Brian M. Ortmann (ORCID: https://orcid.org/0000-0002-3639-0691)
- Nicholas J. Matheson (ORCID: https://orcid.org/0000-0002-3318-1851)
- Thomas J. Mitchell (ORCID: https://orcid.org/0000-0003-0761-9503)
- Jia Jhing Sia (ORCID: https://orcid.org/0000-0003-4750-3417)
- Qian Liang
- James A. C. Bertlin
- Qing Zhang
- Niek Wit
Institutions
- NHS Blood and Transplant (GB)
- University of Cambridge (GB)
- Cancer Research UK Cambridge Center (GB)
- CRUK Lung Cancer Centre of Excellence (GB)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-03-12
- DOI
- https://doi.org/10.1038/s41467-026-70517-w
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Cancer Prevention and Research Institute of Texas
- Wellcome Trust
- Cancer Research UK
- National Institute for Health and Care Research
- Department of Health and Social Care
- Lister Institute of Preventive Medicine
- Evelyn Trust
- NIHR Cambridge Biomedical Research Centre
- National Cancer Institute