RUNX1 and cancer: Given that sporadic RUNX1 mutations are rarely initiating events in leukemia, and RUNX1 deficiency often requires secondary hits such as MLL-ENL, NRAS, and EVI5 mutations [41,42,43], it has been postulated that RUNX1 mutations may trigger genomic instability in human cancers, which in turn, renders such preleukemic cells permissive for the accumulation of tumor-promoting secondary hits.