PMC

Multiple distinct clinical scenarios exist after initial treatment of leukemia. If there is incomplete eradication of leukemia cells (A), the patient would be considered to have some minimal residual disease, and these residual leukemia cells would be able to proliferate and cause relapsed disease with short latency that is genetically similar to the disease at diagnosis. Alternatively, complete eradication of leukemia cells but incomplete targeting of pre-leukemic cells (B) could result in low or undetectable minimal residual disease. However, it remains possible for these pre-leukemic cells to acquire further genetic alterations leading to a genetically divergent relapsed disease with a longer latency (E). The optimal therapeutic situation would be one in which all leukemic and pre-leukemic cells are eradicated (C). Such a scenario would result in the most durable remissions, and potentially, long-term cure of AML (F).

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.