DNAJB1-PRKACA fusion kinase drives tumorigenesis and interacts with β-catenin and the liver regenerative response.

A segmental deletion resulting in DNAJB1- PRKACAgene fusion is now recognized as the signature genetic event of fibrolamellar hepatocellular carcinoma(FL-HCC), a rare but lethal liver cancer that primarily affects adolescents and young adults. Here, we implement CRISPR/ Cas9 genome editingand transposon-mediated somatic gene transfer to demonstrate that expression of both the endogenous fusion protein or a chimeric cDNA leads to the formation of indolent liver tumorsin mice that closely resemble human FL-HCC. Notably, overexpression of the wild type PRKACAwas unable to fully recapitulate the oncogenic activity of DNAJB1- PRKACA, implying that FL-HCC does not simply result from enhanced PRKACAexpression. Tumorigenesis was significantly enhanced by genetic activation of β-catenin, an observation supported by evidence of recurrent Wnt pathway mutations in human FL-HCC, as well as treatment with hepatotoxin3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), which causes tissue injury, inflammation and fibrosis. Our study validates the DNAJB1- PRKACAfusion kinase as an oncogenic driver and candidate drug target for FL-HCC. Practical and scalable mouse models of this disease serve as a resource to further explore tumor development and treatment.