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Rac GTPases as key regulators of p210-BCR-ABL-dependent leukemogenesis

Leukemia volume 22, pages 898–904 (2008)Cite this article

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.

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Acknowledgements

This work was supported by the National Institute of Health grant numbers HL69974 and DK62757 (DAW), Leukemia Lymphoma Society grant 6152-06 (DAW), T32 HD046387 (EKT) and the Department of Defense New Investigator Award CM064050 (JAC). DAW and YZ may obtain royalties based on milestones set forth in a licensing agreement between Cincinnati Children’s Hospital Medical Center and Amgen related to the development of drug inhibitors of Rac GTPases.

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  1. E K Thomas and J A Cancelas: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Experimental Hematology, Cincinnati Children's Research Foundation, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA

    E K Thomas, J A Cancelas, Y Zheng & D A Williams

  2. Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    J A Cancelas

  3. Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA

    D A Williams

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Correspondence to D A Williams.

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Thomas, E., Cancelas, J., Zheng, Y. et al. Rac GTPases as key regulators of p210-BCR-ABL-dependent leukemogenesis. Leukemia 22, 898–904 (2008). https://doi.org/10.1038/leu.2008.71

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