the authors ... show that the transforming effects of (R)-2-HG are reversible
Mutations in IDH1 and IDH2 that have been isolated in cancer cells alter the function of these enzymes: instead of converting isocitrate to α-ketoglutarate (α-KG), they produce the (R) enantiomer of 2-hyroxyglutarate ((R)-2-HG). Although (R)-2-HG is referred to as an oncometabolite, proof that this product is sufficient to transform cells is lacking. Julie-Aurore Losman, William Kaelin and colleagues examined the effect of a common IDH1 mutant (IDH1-R132H) on TF-1 cells — a human erythroleukaemia cell line that is dependent on granulocyte–macrophage colony-stimulating factor (GM-CSF) for survival and proliferation, and that differentiates in the presence of erythropoietin (EPO). Lentiviral expression of wild-type IDH1, IDH1-R132H or a catalytically inactive form of IDH1 showed that IDH1-R132H induced cytokine independence and loss of EPO-mediated differentiation. A similar loss of differentiation was evident in mouse granulocyte–macrophage progenitor cells that express a conditional (oestrogen-dependent) oestrogen receptor (ER)–HOXB8 fusion protein. In the absence of oestrogen these cells differentiate and express monocyte markers, but this response is blunted in cells expressing IDH1-R132H. So, is (R)-2-HG able to cause these effects? The use of cell membrane-permeable forms of (R)-2-HG and the (S) enantiomer ((S)-2-HG) showed that only (R)-2-HG induced cytokine independence and a loss of differentiation in TF-1 cells and loss of differentiation in ER–HOXB8 cells.
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