Mutant IDH regulates glycogen metabolism from early cartilage development to malignant chondrosarcoma formation

Sinthu Pathmanapan, Raymond Poon, Tomasa Barrientos De Renshaw, Puviindran Nadesan, Makoto Nakagawa, Gireesh A. Seesankar, Adrian Kwan Ho Loe, Hongyuan H. Zhang, Joan J. Guinovart, Jordi Duran, Christopher B. Newgard, Jay S. Wunder, Benjamin A. Alman

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Resum

Chondrosarcomas are the most common malignancy of cartilage and are associated with somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes. Somatic IDH mutations are also found in its benign precursor lesion, enchondromas, suggesting that IDH mutations are early events in malignant transformation. Human mutant IDH chondrosarcomas and mutant Idh mice that develop enchondromas investigated in our studies display glycogen deposition exclusively in mutant cells from IDH mutant chondrosarcomas and Idh1 mutant murine growth plates. Pharmacologic blockade of glycogen utilization induces changes in tumor cell behavior, downstream energetic pathways, and tumor burden in vitro and in vivo. Mutant IDH1 interacts with hypoxia-inducible factor 1α (HIF1α) to regulate expression of key enzymes in glycogen metabolism. Here, we show a critical role for glycogen in enchondromas and chondrosarcomas, which is likely mediated through an interaction with mutant IDH1 and HIF1α.

Idioma originalAnglès
Número d’article112578
Nombre de pàgines49
RevistaCell Reports
Volum42
Número6
DOIs
Estat de la publicacióPublicada - 27 de juny 2023
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