A recent report of characteristic methylation anomalies in DNMT3AR882H/+ or DNMT3AR882C/+ cases of AML that are not present in DNMT3A+/+ cases [52] highlights the issue: while the data strongly indicate that abnormal genomic methylation patterns are involved in the progression to AML, the methylation changes actually directly involved in leukemogenesis will be difficult to define. This evidence concerns the gene DNMT3A and acute myeloid leukemia.