IDH1 and IDH2 (Isocitrate Dehydrogenase 1 and 2) mutants are common in several cancers, including leukemias, and overproduce the (R)-enantiomer of 2-hydroxyglutarate [(R)-2-HG]. Elucidating the role of IDH mutations and (R)-2-HG in leukemogenesis has been hampered by a lack of appropriate cell-based models. Here we show that a canonical IDH1 mutant, IDH1 R132H, promotes cytokine-independence and blocks differentiation in hematopoietic cells. These effects can be recapitulated by (R)-2-HG, but not (S)-2-HG, despite the fact that (S)-2-HG more potently inhibits enzymes previously linked to the pathogenesis of IDH mutant tumors, such as TET2 (Ten Eleven Translocation 2). We provide evidence that this paradox relates to the ability of (S)-2-HG, but not (R)-2-HG, to inhibit the EglN (Egg-laying Defective Nine) prolyl hydroxylases and, importantly, show that transformation by (R)-2-HG is reversible.
review. Sequence searching in public databases has College of Physicians and Surgeons revealed six other family members that have a central Columbia University SH2 domain and a C-terminal SOCS box. The N-terminal New York, New York 10032regions of these proteins are highly variable (Figure 1).
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