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.

Figure 1

Model of activation of Rac GTPases in BCR-ABL-induced leukemogenesis. The various pathways of activation downstream of p210-BCR-ABL are indicated with different color codes. Gray-shaded areas indicate molecules or domains with guanine nucleotide exchange factor (GEF) activity. The Dbl and pleckstrin homology (Dbl and PH) domains, only present in p210-BCR-ABL, activate Rho GTPases directly. The SH3 domain in both p190- and p210-BCR-ABL activates p95Vav (Vav1). Y177/Y412, tyrosine residues that can be phosphorylated; Dbl, Rac GTPase exchange factor; SH2/SH3, Src homology domains; DD; dimerization domain; DBD, DNA-binding domain; ABD, actin-binding domain.