Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer

Mutations inisocitrate dehydrogenase 1 (IDH1) andIDH2 areamong the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer1-5. Mutant IDH proteins in IHCCand othermalignancies acquire an abnormal enzymatic activity allowing themto convert a-ketoglutarate (aKG) to 2-hydroxyglutarate (2HG), which inhibits the activity ofmultiple aKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellularmatrixmaturation6-10.However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear.HereweshowthatmutantIDHblocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF-4a, a master regulator of hepatocyte identityandquiescence.Correspondingly, genetically engineeredmousemodels expressingmutant IDHin the adult liver show an aberrant response to hepatic injury, characterized by HNF-4a silencing, impaired hepatocyte differentiation, andmarkedly elevated levels of cell proliferation. Moreover,IDH and Kras mutations, genetic alterations that co-exist in a subset of human IHCCs4,5, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression tometastaticIHCC. These studies provide a functional link between IDHmutations, hepatic cell fate, and IHCC pathogenesis, and present a novel genetically engineered mouse model of IDH-driven malignancy.