SMAD3 and acute myeloid leukemia: In addition to HOX genes HOXB2-5, HOXB8, and HOXA1, additional genes with concomitant gain of methylation and loss of expression in both ‘pan-HOXA’ and ‘anterior-only’ tumors included the retinoic acid responsive genes GPRC5C [33] and ITM2B [34] as well as the transcription factors SMAD3 and SLIT3. A gene significantly methylated and repressed in ‘pan-HOXA’ tumors only was PHF23, a frequent fusion partner with NUP98 in acute myeloid leukemia (AML) that has been shown to enforce HOXA9-10 expression by protecting activating H3K4Me3 marks and blocking EZH2 mediated HOX-gene repression [35].