The role of Rac and Rho GTPases in the development of myeloid leukemia

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In Acute myeloid leukemia (AML) the malignant cells retain considerable similarity to normal lymphohematopoetic stem cells including the ability to self-renewal. It is this transformed cell population that needs to be eradicated to achieve sustained remission. It has been demonstrated recently that GTPase family proteins not only play critical roles on function and development of hematopoetic cells but also contribute to leukemic transformation of myeloid cells. New Rac-inhibitors selectively targeting these molecules are currently under investigation. We therefore propose to assess the role of small GTPases as potential additional target molecules in AML and their association with cytogenetic alterations as well as their prognostic value in this disease. The effects of RhoH and RhoG expression and Rac activation status will be studied by western blot and Rac pull down experiments as well as retrovirally altered overexpression of Rho cDNA or Rho downregulation utilizing siRNA or “gene k.o.” – technology. AML cell survival, apoptosis, proliferation and cell cycle control will be evaluated in parallel. In vitro studies will initially use established AML cell lines before proceeding to primary AML cells. Additional in vivo studies will be performed in transgenic murine leukemia models and by xenotransplantation of primary AML cells into immunodeficient mice that will furthermore allow to evaluate the effect of Rac-inhibitors on disease progression.