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VHL synthetic lethality screens uncover CBF-β as a negative regulator of STING.

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: James Williamson

LAB HEAD: James Nathan

PROVIDER: PXD074426 | Pride | 2026-02-13

REPOSITORIES: Pride

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			Action	DRS
	JB-JN_VHL-CBFb_F01.mgf	Mgf
	JB-JN_VHL-CBFb_F01.raw	Raw
	JB-JN_VHL-CBFb_F02.mgf	Mgf
	JB-JN_VHL-CBFb_F02.raw	Raw
	JB-JN_VHL-CBFb_F03.mgf	Mgf

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VHL synthetic lethality screens uncover CBF-β as a negative regulator of STING

Project description: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.

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