Targeting Immunophenotypic Markers on Leukemic Stem Cells: How Lessons from Current Approaches and Advances in the Leukemia Stem Cell (LSC) Model Can Inform Better Strategies for Treating Acute Myeloid Leukemia (AML)

Abstract

Therapies targeting cell-surface antigens in acute myeloid leukemia (AML) have been tested over the past 20 years with limited improvement in overall survival. Recent advances in the understanding of AML pathogenesis support therapeutic targeting of leukemia stem cells as the most promising avenue toward a cure. In this review, we provide an overview of the evolving leukemia stem cell (LSC) model, including evidence of the cell of origin, cellular and molecular disease architecture, and source of relapse in AML. In addition, we explore limitations of current targeted strategies utilized in AML and describe the various immunophenotypic antigens that have been proposed as LSC-directed therapeutic targets. We draw lessons from current approaches as well as from the (pre)-LSC model to suggest criteria that immunophenotypic targets should meet for more specific and effective elimination of disease-initiating clones, highlighting in detail a few targets that we suggest fit these criteria most completely.

Figure 1.

Selective pressure model of acute myeloid leukemia (AML). A proposed model showing transformation of the hematopoietic stem cell (HSC) pool from normal to malignant. “Normal” HSCs are shown in gray. Myeloid (M) and lymphoid (L) biased stem cells are present, as well as unbiased HSCs (represented as equal proportion M and L). Different aberrations such as mutations (colored lightning bolts) are associated with certain HSC subclones that can be detected, for example, by sequencing (clonal hematopoiesis) (A). These aberrations can occur in a lineage-biased stem cell or may confer a lineage bias. Selective pressures such as inflammation, immune surveillance, and niche effects may give certain HSC clones an advantage over others (i.e., inflammation gives the clone with an orange mutation a selective advantage over normal HSCs). Clonal evolution is also potentially further driven by additional mutations and aging-associated phenomena such as chronic inflammation and myeloid bias (B). For example, an inflammatory microenvironment created by pre-leukemic clones can promote selective expansion of mutated clones over normal HSCs (C). Together, these factors can eventually lead to malignant transformation and achievement of clonal dominance of particular stem cell subclones, and consecutive uncontrolled proliferation of leukemic bulk clones (shown as royal blue and bright green cells).

Figure 2.

Importance of target functionality for therapeutic targeting. (A) If a therapeutic target does not have a cell-intrinsic function in leukemic cells, leukemic cells may be able to escape elimination by the drug through down-regulating the target. (B) If a target provides essential signaling in leukemic cells but is dispensable for normal cells, even normal cells expressing the target could be spared by a drug that inhibits the target's function (but would likely be eliminated with an immunotherapeutic approach or antibody–drug conjugate).