Right on target: eradicating leukemic stem cells

Abstract

Less than a third of adults with acute myeloid leukemia (AML) are cured by current treatments, emphasizing the need for new approaches to therapy. The discovery over a decade ago that myeloid leukemias originate from rare stem-like cells that can transfer the disease to immunodeficient mice suggested that these 'leukemia stem cells' (LSCs) are responsible for relapse of leukemia following conventional or targeted cancer therapy and that eradication of LSCs might be necessary to cure the disease permanently. Several recent studies have provided insight into the signaling pathways underlying the LSC phenotype and have also described approaches to eliminate LSCs with antibodies. Here, we review recent advances in LSC research and discuss novel therapeutic strategies to specifically target LSCs.

Figure 1

Diagram of normal myeloid development and the relationship to leukemic cells and LSCs. Multipotential stem and progenitor cells, including long-term repopulating (LTR) and short-term repopulating (STR) stem cells and multipotential progenitors (MPPs), are depicted in blue on the left. Committed progenitors, including common myeloid progenitors (CMPs), granulocyte–macrophage progenitors (GMPs), megakaryocyte–erythroid progenitors (MEPs) and the colony-forming units (CFUs) for granulocytes (CFU-Gs), macrophages (CFU-Ms), erythroid (CFU-E) and megakaryocytes (CFU-Mks), are depicted in orange in the middle. Differentiating myeloid cells, recognizable by their distinct morphology, are shown at the right. The malignant cells in acute and chronic myeloid leukemia are indicated by red boxes; leukemic blasts for the different FAB subclasses of AML (M0 through M7) correspond approximately to the different normal blasts in each lineage, whereas CML chronic-phase cells correspond to terminally differentiated granulocytes. By contrast, the LSCs for acute and chronic myeloid leukemias are restricted to rare multi-potential and committed progenitors, as indicated by the blue boxes.

Figure 2

Cell-surface markers and therapeutic targets of myeloid leukemia stem cells. (a) Diagram of a normal hematopoietic stem cell (HSC), which expresses the cell surface markers CD34, CD90 and CD117 (right) [23]. Some of the signaling pathways known to promote expansion and self-renewal of HSCs include WNT–frizzled–b-catenin [44], Jagged-Notch [43], Hedgehog–Patched-–Smoothened–Gli [42] and HoxA9/HoxB4 [40,41]. The polycomb group protein Bmi-1 promotes HSC maintenance through inhibition of the cell cycle and apoptosis regulators p16 and ARF [45]. (b) Diagram of a hypothetical myeloid leukemia stem cell (LSC), some of which can express the cellsurface markers CD33 [27], CD123 [26] and CLL-1 [28] (left). Potential agents and strategies for the eradication of LSCs are depicted in red and include antibodies and fusion proteins as well as small-molecule inhibitors. For details, see text.