Whereas mutations in epigenetic modifiers such as DNMT3A, ASXL1, IDH2, and TET2 have been consistently identified as early mutations in studies examining the temporal order of mutation acquisition in sporadic AML (Jan et al., 2012; Krönke et al., 2013; Corces-Zimmerman et al., 2014; Shlush et al., 2014; Hirsch et al., 2016; Papaemmanuil et al., 2016), RUNX1 mutations have rarely been identified as “early” or “initiating” mutations in these studies (Jan et al., 2012; Corces-Zimmerman et al., 2014; Shlush et al., 2014; Hirsch et al., 2016; Papaemmanuil et al., 2016). The gene discussed is DNMT3A; the disease is acute myeloid leukemia.