While NUP98-NSD1 induced leukemic transformation through direct targeting and epigenetic modulation of AML-promoting “stemness” genes (HOX gene clusters and MEIS1) (30), a DNMT3A hotspot mutation (DNMT3AR882H) was recently found to focally suppress DNA methylation at cis-regulatory elements of these genes thereby promoting their transcription activation (96). The gene discussed is NUP98; the disease is acute myeloid leukemia.