ReviewTranslating leukemia stem cells into the clinical setting: Harmonizing the heterogeneity

- Relapses occur in AML because current treatments do not target and eliminate leukemia stem cells clinically.
- Several lines of evidence now question the clinical relevance of leukemia cells that engraft in immunocompromised mice, the “gold standard” for identifying LSCs.
- The leukemia clone's most immature phenotype is heterogeneous for CD34, CD38, and ALDH expression, but correlates with genetically defined risk groups and outcomes.
- Identifying the most immature phenotype within a patient's leukemia and studying this population for actionable targets may bypass the reliance on mouse models to identify LSCs.

Considerable evidence suggests that rare leukemia cells with stem cell features, including self-renewal capacity and drug resistance, are primarily responsible for both disease maintenance and relapses. Traditionally, these so-called leukemia stem cells (LSCs) have been identified in the laboratory by their ability to engraft acute myeloid leukemia (AML) into immunocompromised mice. For many years, only those rare AML cells characterized by a hematopoietic stem cell (HSC) CD34+CD38- phenotype were believed capable of generating leukemia in immunocompromised mice. However, more recently, significant heterogeneity in the phenotypes of those AML cells that can engraft immunocompromised mice has been demonstrated. AML cells that engraft immunocompromised mice have also been shown to not necessarily represent either the founder clone or those cells responsible for relapse. A recent study found that the most immature phenotype present in an AML correlated with genetically defined risk groups and outcomes, but was heterogeneous. Patients with AML cells expressing a primitive HSC phenotype (CD34+CD38- with high aldehyde dehydrogenase activity) manifested significantly lower complete remission rates, as well as poorer event-free and overall survivals. Leukemias in which the most primitive cells displayed more mature phenotypes were associated with better outcomes. The strong clinical correlations suggest that the most immature phenotype detectable within a patient's AML might serve as a biomarker for “clinically relevant” LSCs.