TY - JOUR
T1 - Mutant IDH inhibits HNF-4α to block hepatocyte differentiation and promote biliary cancer
AU - Saha, Supriya K.
AU - Parachoniak, Christine A.
AU - Ghanta, Krishna S.
AU - Fitamant, Julien
AU - Ross, Kenneth N.
AU - Najem, Mortada S.
AU - Gurumurthy, Sushma
AU - Akbay, Esra A.
AU - Sia, Daniela
AU - Cornella, Helena
AU - Miltiadous, Oriana
AU - Walesky, Chad
AU - Deshpande, Vikram
AU - Zhu, Andrew X.
AU - Heze, Aram F.
AU - Yen, Katharine E.
AU - Straley, Kimberly S.
AU - Travins, Jeremy
AU - Popovici-Muller, Janeta
AU - Gliser, Camelia
AU - Ferrone, Cristina R.
AU - Apte, Udayan
AU - Llovet, Josep M.
AU - Wong, Kwok Kin
AU - Ramaswamy, Sridhar
AU - Bardeesy, Nabeel
PY - 2014/9
Y1 - 2014/9
N2 - 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.
AB - 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.
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U2 - 10.1038/nature13441
DO - 10.1038/nature13441
M3 - Article
C2 - 25043045
AN - SCOPUS:84907033777
VL - 513
SP - 110
EP - 152
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7516
ER -