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

Leukemia volume 23, pages 25–42 (2009)Cite this article

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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Acknowledgements

JAM and LSS have been supported in part by a grant from the NIH (R01098195). JB was supported in part by the Deutsche Krebshilfe. MC, MM and AT have been supported in part from grants from Associazione Italiana Ricerca sul Cancro (AIRC). FN has been supported in part by the grant PRIN from Ministero dell’Istruzione, dell’Università e della Ricerca. ML has been in part supported by the grant from Lega Italiana per la Lotta contro i Tumori. AMM has been supported in part by grants from the CARISBO Foundation and the Progetti Strategici Università di Bologna EF2006.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA

    N Misaghian, L S Steelman, F E Bertrand & J A McCubrey

  2. Department of Biomedical Sciences, University of Catania, Catania, Italy

    G Ligresti, M Libra, F Nicoletti & F Stivala

  3. Division of Hematology and Oncology, Department of Medicine, Georg-August University, Göttingen, Germany

    J Bäsecke

  4. Regina Elena Cancer Center, Rome, Italy

    M Milella

  5. Department of Cellular Biotechnologies and Hematology, University ‘La Sapienza’ of Rome, Rome, Italy

    A Tafuri

  6. Consiglio Nazionale delle Ricerche, Istituto di Biomedicina e Immunologia Molecolare ‘Alberto Monroy’, Palermo, Italy

    M Cervello

  7. Department of Human Anatomical Sciences. University of Bologna, Bologna, Italy

    A M Martelli

  8. IGM/CNR, c/o IOR, Bologna, Italy

    A M Martelli

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  1. N Misaghian
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  2. G Ligresti
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  3. L S Steelman
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  4. F E Bertrand
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  6. M Libra
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  9. M Milella
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  10. A Tafuri
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  12. A M Martelli
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  13. J A McCubrey
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Correspondence to J A McCubrey.

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Misaghian, N., Ligresti, G., Steelman, L. et al. Targeting the leukemic stem cell: the Holy Grail of leukemia therapy. Leukemia 23, 25–42 (2009). https://doi.org/10.1038/leu.2008.246

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  • DOI: https://doi.org/10.1038/leu.2008.246

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