title: Rac GTPases as key regulators of p210-BCR-ABL-dependent leukemogenesis.
abstract: Chronic myelogenous leukemia (CML) is a malignant disease characterized by expression of p210-BCR-ABL, the product of the Philadelphia chromosome. Survival of CML patients has been significantly improved with the introduction of tyrosine kinase inhibitors that induce long-term hematologic remissions. However, mounting evidence indicates that the use of a single tyrosine kinase inhibitor does not cure this disease due to the persistence of p210-BCR-ABL at the molecular level or the acquired resistance in the stem cell compartment to individual inhibitors. We have recently shown in a murine model that deficiency of the Rho GTPases Rac1 and Rac2 significantly reduces p210-BCR-ABL-mediated proliferation in vitro and myeloproliferative disease in vivo, suggesting Rac as a potential therapeutic target in p210-BCR-ABL-induced disease. This target has been further validated using a first-generation Rac-specific small molecule inhibitor. In this review we describe the role of Rac GTPases in p210-BCR-ABL-induced leukemogenesis and explore the possibility of combinatorial therapies that include tyrosine kinase inhibitor(s) and Rac GTPase inhibitors in the treatment of CML.
authors: Division of Experimental Hematology, Cincinnati Children's Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors: E K
authors: EK
authors: Thomas
authors: J A
authors: JA
authors: Cancelas
authors: Y
authors: Y
authors: Zheng
authors: D A
authors: DA
authors: Williams
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000209:etiology*; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors; D000097766:RAC2 GTP-Binding Protein
chemical_list: D016044:Fusion Proteins, bcr-abl; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein