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.