Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer1,2,3,4,5. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert α-ketoglutarate (αKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple αKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation6,7,8,9,10. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF-4α, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models expressing mutant IDH in the adult liver show an aberrant response to hepatic injury, characterized by HNF-4α silencing, impaired hepatocyte differentiation, and markedly 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 to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis, and present a novel genetically engineered mouse model of IDH-driven malignancy.
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Gene Expression Omnibus
Affymetrix Mouse 420Av2 DNA microarray data have been deposited in the Gene Expression Omnibus under accession number GSE57002.
We thank R. Mostoslavsky, L. Ellisen, A. Kimmelman, and members of the Bardeesy laboratory for valuable input. We also thank S. Thorgeirsson and J. Andersen for sharing unpublished data sets. This work was supported by grants from TargetCancer Foundation and the National Institutes of Health (R01CA136567-02 and P50CA1270003) to N.B. N.B. holds the Gallagher Endowed Chair in Gastrointestinal Cancer Research at Massachusetts General Hospital. S.K.S. is the recipient of a Cholangiocarcinoma Foundation/Conquer Cancer Foundation of ASCO Young Investigator Award, and an American Cancer Society Postdoctoral Fellowship (PF-13-294-01-TBG). C.A.P. is the recipient of a Canadian Institutes of Health Research postdoctoral fellowship. N.B., J.M.L. and D.S are members of the Samuel Waxman Cancer Research Foundation Institute Without Walls. J.M.L. and D.S. are supported by the Asociación Española Contra el Cáncer (AECC).
Extended data figures
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About this article
Cell Research (2018)