Summary: Researchers have uncovered a new genetic cause of brain cancers and leukemia.
Source: University of Montreal.
Brain cancer and leukemia are two potentially fatal diseases that affect thousands of Canadians each year. But a joint study conducted by researchers Frederick Antoine Mallette, of the Maisonneuve-Rosemont Hospital Research Centre and the University of Montreal, and Marc-Étienne Huot, of Laval University, and published in the prestigious scientific journal Nature Communications has uncovered new molecular causes of brain cancer and leukemia.
We already knew the existence of a mutation phenomenon involving certain metabolic enzymes called isocitrate dehydrogenases 1 and 2 (IDH1/2) in various forms of brain cancer, including gliomas and glioblastomas, and in acute myeloid leukemia. Although the mutated forms of IDH1/2 appear to contribute to cancer formation, until now we had only limited understanding of the ways in which these metabolic defects caused cancer. Research conducted by Mélissa Carbonneau, a master’s student in Professor Mallette’s laboratory, has helped to better understand the effect of IDH1/2 mutations in cancer by demonstrating their role in activating the pathways involved in cell proliferation and survival.
“With the identification of the molecular modes of action that contribute to cancer in patients carrying IDH1/2 mutations, it is now possible to consider personalized treatment to potentially improve therapeutic response,” said Dr. Mallette.
It is estimated that in 2015, 3,000 Canadians were diagnosed with brain and spinal cord cancer, and 6,200 Canadians were diagnosed with leukemia.
Funding: The study was conducted with funding from the Canadian Institutes of Health Research, the Canada Research Chairs program, the Cole Foundation, the Maisonneuve-Rosemont Hospital Research Centre, and the Fonds de recherche du Québec – Santé.
Source: Florence Meney – University of Montreal
Image Source: NeuroscienceNews.com image is adapted from the University of Montreal press release.
Original Research: Full open access research for “The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway” by Mélissa Carbonneau, Laurence M. Gagné, Marie-Eve Lalonde, Marie-Anne Germain, Alena Motorina, Marie-Christine Guiot, Blandine Secco, Emma E. Vincent, Anthony Tumber, Laura Hulea, Jonathan Bergeman, Udo Oppermann, Russell G. Jones, Mathieu Laplante, Ivan Topisirovic, Kevin Petrecca, Marc-Étienne Huot and Frédérick A. Mallette in Nature Communications. Published online September 14 2016 doi:10.1038/ncomms12700
The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway
The identification of cancer-associated mutations in the tricarboxylic acid (TCA) cycle enzymes isocitrate dehydrogenases 1 and 2 (IDH1/2) highlights the prevailing notion that aberrant metabolic function can contribute to carcinogenesis. IDH1/2 normally catalyse the oxidative decarboxylation of isocitrate into α-ketoglutarate (αKG). In gliomas and acute myeloid leukaemias, IDH1/2 mutations confer gain-of-function leading to production of the oncometabolite R-2-hydroxyglutarate (2HG) from αKG. Here we show that generation of 2HG by mutated IDH1/2 leads to the activation of mTOR by inhibiting KDM4A, an αKG-dependent enzyme of the Jumonji family of lysine demethylases. Furthermore, KDM4A associates with the DEP domain-containing mTOR-interacting protein (DEPTOR), a negative regulator of mTORC1/2. Depletion of KDM4A decreases DEPTOR protein stability. Our results provide an additional molecular mechanism for the oncogenic activity of mutant IDH1/2 by revealing an unprecedented link between TCA cycle defects and positive modulation of mTOR function downstream of the canonical PI3K/AKT/TSC1-2 pathway.
“The oncometabolite 2-hydroxyglutarate activates the mTOR signalling pathway” by Mélissa Carbonneau, Laurence M. Gagné, Marie-Eve Lalonde, Marie-Anne Germain, Alena Motorina, Marie-Christine Guiot, Blandine Secco, Emma E. Vincent, Anthony Tumber, Laura Hulea, Jonathan Bergeman, Udo Oppermann, Russell G. Jones, Mathieu Laplante, Ivan Topisirovic, Kevin Petrecca, Marc-Étienne Huot and Frédérick A. Mallette in Nature Communications. Published online September 14 2016 doi:10.1038/ncomms12700