title: Targeting the leukemic stem cell: the Holy Grail of leukemia therapy.
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.
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC 27858, USA.
authors.forename: N
authors.initials: N
authors.lastname: Misaghian
authors.forename: G
authors.initials: G
authors.lastname: Ligresti
authors.forename: L S
authors.initials: LS
authors.lastname: Steelman
authors.forename: F E
authors.initials: FE
authors.lastname: Bertrand
authors.forename: J
authors.initials: J
authors.lastname: Bäsecke
authors.forename: M
authors.initials: M
authors.lastname: Libra
authors.forename: F
authors.initials: F
authors.lastname: Nicoletti
authors.forename: F
authors.initials: F
authors.lastname: Stivala
authors.forename: M
authors.initials: M
authors.lastname: Milella
authors.forename: A
authors.initials: A
authors.lastname: Tafuri
authors.forename: M
authors.initials: M
authors.lastname: Cervello
authors.forename: A M
authors.initials: AM
authors.lastname: Martelli
authors.forename: J A
authors.initials: JA
authors.lastname: McCubrey
mesh_terms: D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D016896:Treatment Outcome
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