Journal
LEUKEMIA
Volume 23, Issue 1, Pages 25-42Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2008.246
Keywords
drug transporters; drug resistance; tumor-initiating cell; stem cells; targeted therapy
Categories
Funding
- NIH [R01098195]
- Deutsche Krebshilfe
- Associazione Italiana Ricerca sul Cancro (AIRC)
- PRIN from Ministero dell'Istruzione, dell'Universita e della Ricerca
- Lega Italiana per la Lotta contro i Tumori
- CARISBO Foundation
- Progetti Strategici Universita di Bologna [EF2006]
- NATIONAL CANCER INSTITUTE [R01CA098195] Funding Source: NIH RePORTER
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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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