Sequential acquisition of mutations during clonal evolution is illustrated by changes in color. Multiple scenarios for leukemic evolution exist. The simplest model posits that the first mutation would occur in a normal HSC (A) that retains the ability to self-renew. Alternatively, the first mutation could occur in a more differentiated cell and could confer self-renewal to this previously non-self-renewing cell (B). If, however, the first mutation were to occur in a differentiated cell but not confer self-renewal, this mutation would likely be lost due to exhaustion of this lineage (C). Subsequent mutations accumulate in this self-renewing HSC lineage. At each stage of evolution, these self-renewing cells retain the ability to produce differentiated progeny of both the myeloid and lymphoid lineages (D). Eventually, one or a few additional mutations lead to the generation of a fully leukemic cell. This mutational event could occur in a bonafide HSC (E) or in a progenitor cell (F). The resultant leukemia cell loses the capability to differentiate into multiple cellular lineages.