Biology and relevance of human acute myeloid leukemia stem cells

Abstract

Evidence of human acute myeloid leukemia stem cells (AML LSCs) was first reported nearly 2 decades ago through the identification of rare subpopulations of engrafting cells in xenotransplantation assays. These AML LSCs were shown to reside at the apex of a cellular hierarchy that initiates and maintains the disease, exhibiting properties of self-renewal, cell cycle quiescence, and chemoresistance. This cancer stem cell model offers an explanation for chemotherapy resistance and disease relapse and implies that approaches to treatment must eradicate LSCs for cure. More recently, a number of studies have both refined and expanded our understanding of LSCs and intrapatient heterogeneity in AML using improved xenotransplant models, genome-scale analyses, and experimental manipulation of primary patient cells. Here, we review these studies with a focus on the immunophenotype, biological properties, epigenetics, genetics, and clinical associations of human AML LSCs and discuss critical questions that need to be addressed in future research.

Figure 1.

Timeline of human AML engraftment models. Historical timeline is indicated with immunodeficient mouse models used for AML engraftment. The panel below indicates the subtypes of AML exhibiting engraftment in the models along with the relevant references. Note that as the immunodeficient mouse models improved the engraftment of more AML subtypes was observed. APL, acute promyelocytic leukemia; NK, normal karyotype; MISTR-G, RAG2-IL2R-γ null with human M-CSF, IL-3, GM-CSF, SIRPA, and TPO; MLL, mixed-lineage leukemia; NSG, NOD-SCID-IL2R-γ null; NS-B2M, NOD-SCID-beta2-microglobulin null; NSG-S, NSG expressing human IL-3, GM-CSF, and stem cell factor.

Figure 2.

Immunophenotype and biological characteristics of CD34⁺and CD34⁻AML LSCs. (A) AML LSCs in CD34⁺ AML are primarily detected within LMPP-like (CD34⁺CD38⁻CD90⁻CD45RA⁺) and GMP-like (CD34⁺CD38⁺CD123⁺CD45RA⁺) subpopulations when engrafted into NSG mice. Less frequently they are detected in a dominant MPP-like (CD34⁺CD38⁻CD90⁻CD45RA⁻) subpopulation. Nevertheless, the stability of these markers after chemotherapy has not been rigorously tested, and there is likely to be considerable plasticity between these populations. LSCs are resistant to chemotherapy and give rise to non-LSC leukemic cells. OX-PHOS, oxidative phosphorylation. (B) AML LSCs in CD34⁻ AML are primarily detected within a precursor GM-like (CD34⁻CD117⁺CD244^+/−) subpopulation based on recent studies. Upon engraftment, these cells give rise to non-LSC leukemic cells. These findings have yet to be validated in additional studies but indicate a striking contrast with CD34⁺ AML and possibly a more mature myeloid cell of origin that has acquired self-renewal properties.

Figure 3.

Hierarchical relationships between LSCs in CD34⁺and CD34⁻AML at diagnosis. Xenograft models suggest that CD34⁺ AML is arranged in a semihierarchical structure resembling normal hematopoiesis (left). In many patients, there is an increased LSC frequency in the CD34⁺CD38⁻ population, which in turn gives rise to a CD34⁺CD38⁺ population with a reduced LSC frequency, but reversible plasticity is likely to be present in many cases. In infrequent cases, CD34⁻ cells also contain rare LSCs. In CD34⁻ AML, CD34⁺ and CD34⁻ populations have similar LSC frequencies and gene expression profiles that most resemble precursor GM cells (right). The CD34⁻ LSCs may express progenitor markers such as CD117 and myeloid antigens such as CD15 and CD244, and both in turn give rise to a non-LSC population with a mature myeloid immunophenotype.