Figure 1.

The role of minimal residual disease, therapy resistance and LSCs in AML relapse development. In normal hematopoiesis (green box), quiescent hematopoietic stem cells (HSCs) with self-renewal capacity give rise to multipotent progenitors (MPPs), which can differentiate towards lymphoid primed multipotent progenitors (LMPPs), common myeloid progenitors (CMPs), common lymphoid progenitors (CLPs), granulocyte-macrophage progenitors (GMPs) and megakaryocyte erythroid progenitors (MEP). These lineage-committed progenitors can produce terminally differentiated lymphoid, myeloid and erythroid blood cells. AML originates from the transformation of normal HSCs, MPPs or more committed progenitors, developing in leukemic stem cells (LSCs) that subsequently can give rise to full-blown leukemia. AML initiated from HSC and MPP highly express the transcription factor EVI-1. At AML diagnosis (blue box), a heterogeneous leukemia cell population with a variety of sensitivities to therapy exists. Moreover, LSCs and normal hematopoietic (stem) cells, responsible for reconstituting the normal healthy blood cells after therapy, co-reside in the patient’s bone marrow. While treatment with standard induction chemotherapy results in complete remission in the majority of AML patients, a population of (chemo)therapy-resistant cells (TRCs) (minimal residual disease) constituting AML cells with leukemia-initiating potential survive the treatment. LSCs with leukemia-initiating potential within MRD could initiate sooner or later a relapse. Instead of (chemo)therapeutic selection of pre-existing subpopulations of LSCs, AML cells might adaptively obtain a leukemia re-initiating cell (LRC)-phenotype upon exposure to treatment.