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Nature. 2014 Sep 4;513(7516):110-4. doi: 10.1038/nature13441. Epub 2014 Jul 2.

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

Author information

  • 11] Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA [2].
  • 2Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
  • 3Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
  • 41] HCC Translational Research Laboratory, Barcelona-Clínic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Catalonia 08036, Spain [2] Mount Sinai Liver Cancer Program, Division of Liver Diseases, Dept of Medicine. Icahn School of Medicine at Mount Sinai, New York 10029, USA [3] Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, and Department of Experimental Oncology, Milan 20133, Italy.
  • 5HCC Translational Research Laboratory, Barcelona-Clínic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Catalonia 08036, Spain.
  • 6Mount Sinai Liver Cancer Program, Division of Liver Diseases, Dept of Medicine. Icahn School of Medicine at Mount Sinai, New York 10029, USA.
  • 7Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
  • 8University of Rochester Medical Center, Rochester, New York 14642, USA.
  • 9Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
  • 101] HCC Translational Research Laboratory, Barcelona-Clínic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, University of Barcelona, Catalonia 08036, Spain [2] Mount Sinai Liver Cancer Program, Division of Liver Diseases, Dept of Medicine. Icahn School of Medicine at Mount Sinai, New York 10029, USA [3] Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia 08010, Spain [4] University of Barcelona, Catalonia 08036, Spain.
  • 111] Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA [2] Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.

Abstract

Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer. 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 maturation. 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 IHCCs, 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.

PMID:
25043045
[PubMed - indexed for MEDLINE]

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