Targeting the leukemic stem cell: the Holy Grail of leukemia therapy
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Date
2009-01
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Authors
Misaghian, Negin
Ligresti, Giovanni
Steelman, L. S.
Bertrand, Fred E.
Basecke, Jorg
Libra, Massimo
Nicoletti, Ferdinando
Stivala, F.
Milella, Michele
Tafuri, A.
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Publisher
East Carolina University
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 chemo-therapeutic drugs and the involvement of growthpromoting
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 smallmolecule
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
รข 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. Originally published Leukemia, Vol. 23, No. 1, Jan 2009
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Leukemia; 23:1 p. 25-42