Mechanisms of response to HMA therapy. (A) Protein network model of a relapsed AML patient with gain-of-function mutations affecting EZH2 and IDH1/2 that predicted for response to the CpG-methylating effects of azacitidine via DNMT1 inhibition. Additionally, loss-of-function mutations in TET2 and L3MBTL1 further increased CpG methylation. The patient achieved a clinical response to azacitidine. Green boxes represent gain of function; blue boxes represent loss of function. (B) An example of a nonresponder to HMA who harbored gain-of-function mutations in IDH1/2 and loss-of-function mutations in ASXL1 and TET2, among others. Green boxes represent gain of function, light blue boxes represent loss of function, and dark blue boxes represent knockdown.