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

• Published in: Leukemia Vol. 23; no. 1; pp. 25 - 42
• Main Authors: Misaghian, N, Ligresti, G, Steelman, L S, Bertrand, F E, Bäsecke, J, Libra, M, Nicoletti, F, Stivala, F, Milella, M, Tafuri, A, Cervello, M, Martelli, A M, McCubrey, J A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2009; Nature Publishing Group
• Subjects: Biological and medical sciences; Bone marrow; Cancer Research; Cancer therapies; Care and treatment; Critical Care Medicine; Diabetes; Drug Delivery Systems - methods; Health aspects; Hematologic and hematopoietic diseases; Hematology; Hematopoietic stem cells; Humans; Immunology; Intensive; Internal Medicine; Leukemia; Leukemia - drug therapy; Leukemia - etiology; Leukemia - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Medicine; Medicine & Public Health; Mutation; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Oncology; review; Risk factors; Signal transduction; Stem cells; Treatment Outcome; Tumors; United States; United States > US; Rome Italy; Italy; drug transporters; stem cells; targeted therapy; tumor-initiating cell; drug resistance; Drug; Treatment resistance; Targeting; Hematology; Targeted therapy; Stem cell; Leukemia; Malignant hemopathy; Treatment; Tumor cell; Cancer
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2008.246

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.