Diverse effects of IDH mutations during leukemogenesis. IDH1/2 mutations induce proleukemogenic effects, which include inhibition of TET2 function, splicing, and HIF signaling. However, several mIDH1/2-induced molecular changes also have antileukemic effects in the right context. These include inhibition of cytochrome c-oxidase (which lowers the mitochondrial apoptotic threshold), inhibition of FTO (which interferes with myc and CEBPα mRNA stability), and increased H3K79 methylation. Increased H3K79 methylation and FTO inhibition are particularly detrimental in KMT2A-rearranged cells, resulting in a failure of short-term cooperation between the 2 oncogenes, as well as 2HG’s toxic effects on KMT2A-rearranged cells (fusions and PTDs). Despite the acute lack of cooperation and 2HG’s toxic effects, a substantial number of KMT2A^PTD patients have IDH1/2 mutations. Two hypothetical and not mutually exclusive models could explain this finding. On one hand, detrimental chromatin and mRNA methylation effects may be rapidly compensated for under selective pressure (left panel). On the other hand, aberrant chromatin and DNA methylation induce dysfunctional hematopoiesis and impaired genome stability, resulting in the emergence of additional mutations (right panel). Eventually, mIDH1/2 AML with a high mutation burden may not be dependent on the initiating genetic event, as suggested by the increased risk of resistance to mIDH1/2 inhibitor in these patients. CNV, copy number variation; SNV, single nucleotide variation.