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Review
. 2009 Jan;23(1):25-42.
doi: 10.1038/leu.2008.246. Epub 2008 Sep 18.

Targeting the leukemic stem cell: the Holy Grail of leukemia therapy

N Misaghian  1 , G Ligresti, L S Steelman, F E Bertrand, J Bäsecke, M Libra, F Nicoletti, F Stivala, M Milella, A Tafuri, M Cervello, A M Martelli, J A McCubrey
Affiliations
Review

Targeting the leukemic stem cell: the Holy Grail of leukemia therapy

N Misaghian et al. Leukemia. 2009 Jan.

Abstract

Since the discovery of leukemic stem cells (LSCs) over a decade ago, many of their critical biological properties have been elucidated, including their distinct replicative properties, cell surface phenotypes, their increased resistance to chemotherapeutic drugs and the involvement of growth-promoting chromosomal translocations. Of particular importance is their ability to transfer malignancy to non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice. Furthermore, numerous studies demonstrate that acute myeloid leukemia arises from mutations at the level of stem cell, and chronic myeloid leukemia is also a stem cell disease. In this review, we will evaluate the main characteristics of LSCs elucidated in several well-documented leukemias. In addition, we will discuss points of therapeutic intervention. Promising therapeutic approaches include the targeting of key signal transduction pathways (for example, PI3K, Rac and Wnt) with small-molecule inhibitors and specific cell surface molecules (for example, CD33, CD44 and CD123), with effective cytotoxic antibodies. Also, statins, which are already widely therapeutically used for a variety of diseases, show potential in targeting LSCs. In addition, drugs that inhibit ATP-binding cassette transporter proteins are being extensively studied, as they are important in drug resistance-a frequent characteristic of LSCs. Although the specific targeting of LSCs is a relatively new field, it is a highly promising battleground that may reveal the Holy Grail of cancer therapy.

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Figures

Figure 1
Figure 1
Overview of normal HSCs and LSCs. LSCs originate from HSCs after various complex genetic mutations. The normal HSC differentiates into functional cells of the lymphoid and myeloid lineages, which perform their biological functions and normally die by apoptosis after an appropriate time period. In contrast, LSCs acquire mutations that allow them to grow and persist in the presence of chemotherapeutic drugs, whereas the majority of the leukemic cells that arise after mutation are unable to continue to proliferate after chemotherapy. Understanding the difference between the LSC and the majority of leukemia that are not LSC may allow the generation of more effective therapeutic strategies. The spiral shading in the HSC, LSC and leukemia cells indicates their ability to propagate indefinitely. The circular arrow indicates self-renewal.
Figure 2
Figure 2
Comparison of LSC and leukemic cells. Although both LSC and leukemic cells originate from HSC, they display distinct differences in terms of cell cycle status and drug transporter activity, which may be responsible for the difference in susceptibility to chemotherapeutic approaches.
Figure 3
Figure 3
Phenotypic difference between AML LSC and AMLs. The bulk of leukemic AMLs differ from AML stem cells in the expression of CD38+ and other genes. This figure is a simplification as some AML (e.g., AML FAB M3; APL) are CD34-. Functionally, these two types of cells also differ in their ability to repopulate NOD-SCID mice. NOD-SCID, non-obese diabetic-severe combined immunodeficient.
Figure 4
Figure 4
Phenotypic differences between CML LSC and CMLs. Although both CML-stem cells and the CML cells contain the BCR-ABL chromosomal translocation, they differ in their proliferative capacity in the presence of certain BCR-ABL inhibitors. This may be due to the presence of certain pre-existing mutations in the BCR-ABL gene in the CML-LSCs. In addition, the CML-LSCs display differences in cytokine expression (IL-3, G-CSF), which may promote autocrine proliferation. The CML-LSC also displayed elevated transporter, Oct-1 and β-catenin pathway expression, which may result in altered proliferation in comparison with CML cells.
Figure 5
Figure 5
Overview of Wnt/β-catenin signaling pathway in leukemia. The Wnt signaling pathway is a central pathway, which results in the transmission of growth-promoting signals that control the activity of β-catenin. Stabilization of β-catenin results in its translocation to the nucleus and promotion of gene transcription by TCF/LEF transcription complex. This can result in the transcription of genes such as Cyclin D, c-Myc, SALL-4, PPARδ and other genes. In the absence of Wnt binding of Frizzled, the multiprotein destruction complex (MDC) is activated and glycogen synthase kinase 3β (GSK-3β) phosphorylates β-catenin and it is targeted for proteasomal degradation. In the presence of Wnt binding, this complex is inactivated. Interactions with other signaling pathways such as PI3K/PTEN/Akt exist, which influence GSK-3β activity (inactivation). This pathway can be activated by Flt-3 and other receptors. Thus, there are interactions between the Wnt and PI3K/PTEN/Akt pathways. Wnt is also postulated to interact with the Notch and other signaling pathways. The Wnt pathway is frequently dysregulated in leukemia. This can occur by mutations at Flt-3, chromosomal translocations, methylation of the promoter regions inhibitory genes such as WIF-1 and many other mechanisms (e.g., mutations at either PI3K or PTEN, which result in the activation of Akt expression).
Figure 6
Figure 6
Targeting the AML-LSC. Potential targets on the AML-LSC are indicated. In general, these targets are not expressed or are expressed at different levels in the AML.
Figure 7
Figure 7
Sites of interaction of signal transduction pathway inhibitors. Various types of inhibitors have been developed to target different molecules involved in signal transduction.
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