VHL synthetic lethality screens uncover CBF-ß as a negative regulator of STING (RNA-Seq).

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 ß (CBF-ß) 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-ß. Mechanistically, CBF-ß loss leads to upregulation of type I interferon signalling, and we uncover a direct inhibitory role for CBF-ß at the STING locus controlling Interferon Stimulated Gene expression. Targeting CBF-ß in kidney cancer both selectively induces tumour cell lethality and may reactivate anti-tumour immune surveillance. Overall design: Total RNA was extracted from cell lines. Library preparation was undertaken with a NEBNext Ultra II RNA Library Preparation kit for polyA transcript selection. These libraries were sequenced on a Illumina NovaSeq 6000 platform