Making Sense of Leukemia Stem Cells: Our Current Understanding and Future Directions.
Authors: Jordan Craig T. 
Published: October 2019

Abstract SCI-36

Understanding the biology of leukemia stem cells (LSC) holds the promise of better defining the pathogenesis of leukemia and developing more effective therapeutic regimens. However, evidence from multiple studies indicates that the properties of LSC can be highly variable. Of particular relevance is the target cell of origin and the specific genetic aberrancies found in each type of leukemia. These two parameters appear to influence properties such as LSC phenotype, frequency, cell cycle status, and drug responsiveness. For example, in chronic phase CML and some types of AML, the LSC compartment seems to be relatively well defined and demonstrates biological properties reminiscent of a normal hematopoietic hierarchy. In contrast, leukemias arising from MLL translocations, and/or lymphoid origins, may be more variable and show much less similarity to normal hematopoiesis. A further confounding factor is the degree to which drug treatment and/or disease progression may contribute to LSC evolution and potential instability during the course of disease. Based on the observations to date, several issues bear consideration. First, the degree to which current models adequately mimic human biology must be carefully evaluated. Syngeneic mouse models provide powerful systems to understand basic biology, but may not adequately reflect the genetic diversity/instability found in human disease. Similarly, whether experimental therapies can be effectively modeled in syngeneic systems is less clear. Conversely, xenograft models permit the analysis of primary human LSC, but may be limited with regard to providing an authentic microenvironment in which to study biology and drug response. Another important variable is the extent to which results in any model system (either syngeneic or xenogeneic) actually predict outcome in human leukemia patients. While the biological sophistication of many systems has greatly improved in the past decade, a major challenge for the future is to determine whether such models will provide a superior means by which to design new therapeutic regimens. Despite the limitations noted above, the available evidence does suggest that more specifically targeting LSC will lead to improved therapeutic outcomes. This observation is true irrespective of the details inherent to any particular form of leukemia. Even if LSC are highly variable, abundant, or unstable, they are no less relevant as a potential drug target. Several exciting lines of investigation from preclinical studies have recently been reported that may provide better eradication of LSC. These approaches include the use of monoclonal antibodies to specific epitopes on LSC, and small molecules designed to block self-renewal pathways and/or leukemia-specific survival mechanisms. As these strategies move into clinical testing, they will serve to better determine the relevance of LSC as a therapeutic target, and provide a key validation test for the utility of current preclinical models.

Disclosures

No relevant conflicts of interest to declare.