RT Journal Article SR Electronic T1 DNAJB1-PRKACA fusion kinase drives tumorigenesis and interacts with β-catenin and the liver regenerative response JF bioRxiv FD Cold Spring Harbor Laboratory SP 192104 DO 10.1101/192104 A1 Edward R. Kastenhuber A1 Gadi Lalazar A1 Darjus F. Tschaharganeh A1 Shauna L. Houlihan A1 Timour Baslan A1 Chi-Chao Chen A1 David Requena A1 Sha Tian A1 Benedikt Bosbach A1 John E. Wilkinson A1 Sanford M. Simon A1 Scott W. Lowe YR 2017 UL http://biorxiv.org/content/early/2017/09/21/192104.abstract AB A segmental deletion resulting in DNAJB1-PRKACA gene 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 editing and 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 tumors in mice that closely resemble human FL-HCC. Notably, overexpression of the wild type PRKACA was unable to fully recapitulate the oncogenic activity of DNAJB1-PRKACA, implying that FL-HCC does not simply result from enhanced PRKACA expression. 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 hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), which causes tissue injury, inflammation and fibrosis. Our study validates the DNAJB1-PRKACA fusion 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.Significance Limited resources are available for the treatment of FL-HCC and a lack of research tools have led to an absence of experimental characterization of the disease. Here, we describe a rapidly scalable method to generate synchronous cohorts of mice bearing FL-HCC tumors. We demonstrate that the Dnajb1-Prkaca gene fusion drives tumorigenesis in mice, and that fusion to DNAJB1 drives FL-HCC initiation more strongly than wild type PRKACA overexpression. The requirement of the PRKACA kinase domain reinforces the potential utility of kinase inhibitors targeting the fusion. By identifying genetic and environmental factors that can enhance the consistency and aggressiveness of disease progression, we reveal biological characteristics of the disease and advance a platform for future pre-clinical studies.