Ohad S. Birk

Kaposi sarcoma (KS), caused by Herpesvirus‐8 (HHV‐8; KSHV), shows sporadic, endemic, and epidemic forms. While familial clustering of KS was previously recorded, the molecular basis of hereditary predilection to KS remains largely unknown. We demonstrate through genetic studies that a dominantly inherited missense mutation in BPTF segregates with a phenotype of classical KS in multiple immunocompetent individuals in two families. Using an rKSHV.219‐infected CRISPR/cas9‐model, we show that BPTF I2012T mutant cells exhibit higher latent‐to‐lytic ratio, decreased virion production, increased LANA staining, and latent phenotype in viral transcriptomics. RNA‐sequencing demonstrated that KSHV infection dysregulated oncogenic‐like response and P53 pathways, MAPK cascade, and blood vessel development pathways, consistent with KS. BPTF I2012T also enriched pathways of viral genome regulation and replication, immune response, and chemotaxis, including downregulation of IFI16 , SHFL HLAs , TGFB1 , and HSPA5 , all previously associated with KSHV infection and tumorigenesis. Many of the differentially expressed genes are regulated by Rel‐NF‐κB, which regulates immune processes, cell survival, and proliferation and is pivotal to oncogenesis. We thus demonstrate BPTF mutation‐mediated monogenic hereditary predilection of KSHV virus‐induced oncogenesis, and suggest BPTF as a drug target.