Understanding mechanisms by which mutated enzymes promote tumor growth may provide new knowledge about how these enzymes’ pathways and their products might serve as novel drug targets.
Many human tumor types, including acute leukemias and brain tumors express mutated forms of the enzyme isocitrate dehydrogenase (IDH1 and IDH2). These mutations result in overproduction of one enantiomer of the enzyme’s product, 2-hydroxyglutarate (2HG): its right enantiomer (R)-2HG. This form of 2HG is thought to alter the epigenetic landscape of cancer cells by inhibiting the activity of other enzymes such as TET2, part of the TET family of 5-methycysotine hydroxylases, thereby ultimately altering gene transcription.
But elucidating the role of IDH mutations and of (R)-2HG in the development of leukemia has been hampered by a lack of appropriate cell-based models, say researchers Julie-Aurore Losman of Dana Farber Cancer Institute and colleagues at Boston’s Brigham and Women’s Hospital, the University of Utah, the University of Oulu in Finland, MIT, Harvard’s Broad Institute, and the Howard Hughes Medical Institute in Chevy Chase, MD.
To investigate mechanisms of how mutant enzymes and their 2HG product promote tumor growth, the researchers determined how the two enantiomers of 2HG might transform cells. They found that (R)-2HG right handed enantiomer, but not the left-handed, (S)-2HG, could transform cells in culture.
The authors had previously reported that stable expression of a tumor-derived mutant IDH1 (IDH1R132H) induces growth-factor independence and blocks EPO-induced differentiation in the human TF-1 erythroleukemia cell line, and that treatment of TF-1 cells with a cell-permeable form of (R)-2HG, TFMB-(R)-2HG, could reproduce this phenotype. And (R)-2HG, they reported, recapitulated this effect despite the fact that (S)-2HG more potently inhibits enzymes known to be linked to the pathogenesis of IDH mutant tumors, such as TET2.
This conundrum, the authors say, appears to be explained by the differential effects of the two enantiomers on EglN1 (Egg-laying Defective Nine) prolyl hydroxylases, with (R)-2HG serving as an agonist and (S)-2HG as an antagonist, and by their observation that loss of EglN1 activity blocks transformation by mutant IDH or loss of TET2.
The authors also said that study results showed that the effects of (R)-2HG are reversible, offering hope that compounds that block (R)-2HG production by IDH mutants will benefit patients. Moreover, they concluded, the relatively rapid reversion of the (R)-2HG transformation phenotypes suggests that the relevant epigenetic marks are more dynamic than previously suspected, or that these phenotypes reflect noncanonical functions of enzymes such as TET2. Additionally, they said, their findings suggest that pharmacological inhibition of EglN1 might also be useful for the treatment of leukemias that harbor IDH or TET2 mutations.