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

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: Cas9 containing cells were transduced with the Toronto KO v3 sgRNA library at an MOI of ~0.3, and after 27 hours selected with puromycin for 7 days. Every two or three days cells were pooled, counted and passaged. After 17 population doublings, genomic DNA was extracted. Lenti viral inserts with the sgRNAs were PCR amplified and sequenced.