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<p>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 (<i>VHL</i>) tumour suppressor gene. Here, we undertake genome-wide CRISPR/Cas9 screening to reveal synthetic lethal interactors of <i>VHL</i>, and uncover that loss of Core Binding Factor β (CBF-β) causes cell death in <i>VHL</i>-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 <i>VHL</i>-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 <i>STING</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月12日

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  • James A. C. Bertlin,
  • Tekle Pauzaite,
  • Qian Liang,
  • Niek Wit,
  • James C. Williamson,
  • Jia Jhing Sia,
  • Nicholas J. Matheson,
  • Brian M. Ortmann,
  • Thomas J. Mitchell,
  • Anneliese O. Speak,
  • Qing Zhang,
  • James A. Nathan

摘要

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.