Following a demonstration that the activity of DOT1L is markedly enhanced by interaction of the enzyme with ubiquitinylated histone 2B (McGinty et al., 2008, 2009), it has now been reported that proliferation of MLL-R leukemia cells was suppressed by knockdown of the ubiquitin ligase RNF20 that ubiquitinylates histone 2B (Wang et al., 2013). The gene discussed is KMT2A; the disease is leukemia.