Mutant IDH prevents hepatocyte differentiation and promotes tumorigenesis via HNF-4α inhibition.
Major finding: Mutant IDH prevents hepatocyte differentiation and promotes tumorigenesis via HNF-4α inhibition.
Mechanism: Mutant IDH-mediated 2HG production and suppression of Hnf4a blocks hepatocyte lineage progression.
Impact: This mouse model offers a tool to evaluate IDH inhibitors in IHCC, a drug-resistant cancer.
Isocitrate dehydrogenase (IDH) 1 and IDH2 are among the most commonly mutated genes in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer characterized by bile duct differentiation. Mutant IDH proteins have previously been shown to gain an abnormal enzymatic activity, mediating the conversion of α-ketoglutarate to 2-hydroxyglutarate (2HG); however, the mechanism by which these mutations induce liver tumorigenesis remain unknown. Saha, Parachoniak, and colleagues investigated the role of IDH mutations in IHCC by first expressing cancer-associated IDH mutants in mouse hepatoblasts, liver progenitor cells that give rise to both hepatocytes and bile duct cells. Unlike wild-type cells, IDH-mutant hepatoblasts failed to undergo hepatocyte differentiation. Chemical inhibition of mutated IDH1 attenuated 2HG levels and rescued hepatocyte lineage progression, whereas treatment with octyl-2HG prevented differentiation of wild-type hepatoblasts, indicating that mutant IDH–mediated suppression of hepatocyte differentiation is 2HG-dependent. Furthermore, IDH-mutant hepatoblasts exhibited decreased expression of targets of hepatocyte nuclear factor 4 α (HNF-4α), a master transcriptional regulator of hepatocyte lineage specification and quiescence. In vivo studies using genetically engineered IDH2-mutant mice demonstrated reduced HNF-4α levels, decreased hepatocyte differentiation, and increased cell proliferation both during aging and following hepatic injury. In addition, expression of oncogenic KRAS in combination with mutant IDH2 cooperatively enhanced progenitor cell expansion and accelerated IHCC development. Together these findings support the notion that suppression of HNF-4α by mutant IDH subverts hepatocyte differentiation and generates a preneoplastic state susceptible to additional mutations enabling tumor progression. Importantly, the IDH-mutant mouse model closely mimics the hallmarks of human IHCC, providing an autochthonous system for testing new treatment options for this disease.