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Deciphering the role of Rho subfamily of GTPases in normal hematopoietic cells and in leukemia cells

Abstract

Acute myeloid leukemia (AML) is a severe hematologic malignancy characterized by the presence of immature hematopoietic cells in the bone marrow that impairs normal formation of blood cells. Mutations in the TP53 tumor suppressor gene (coding for p53 protein) are found in approximately 8% of AML patients and are associated with decreased therapeutic response and survival. Even though the frequency of these mutations is considered relatively low, the inactivation of the p53 signaling pathway by other mechanisms is believed to occur in all cases of AML without TP53 mutation.Recent evidence indicates that the Rho subfamily of GTPases regulates and is directly regulated by p53. Rho subfamily is composed by RhoA, RhoB and RhoC (also known as Rho proteins), which play different roles in normal and neoplastic hematopoiesis. Previous results from our group demonstrated that Rho gene expression is dysregulated and is associated with the presence of TP53 mutations in AML. The expression of Rho in AML was further associated with cellular functions essentially controlled by p53, such as cell cycle, apoptosis, and DNA damage repair.The aim of this study is to investigate RhoA, RhoB and RhoC functions in normal hematopoietic cells and in leukemia cells. To this end, the effects of RhoA, RhoB or RhoC knockdown will be investigated on the proliferation, apoptosis, migration, adhesion, cytoskeletal rearrangements, and DNA damage responses of myeloid cell lines with or without p53 inhibition. RhoA, RhoB and RhoC silencing effects will be also evaluated in the proliferation, apoptosis, migration, adhesion, and global gene expression (RNAseq) of normal hematopoietic cell progenitors. In addition, the relation between alterations in the p53 signaling pathway and Rho expression will be explored in primary cells from AML patients.Results from this project will contribute 1) to elucidate RhoA, RhoB and RhoC functions in normal hematopoietic cells and in leukemia cells, 2) to clarify if these functions depend on p53 signaling pathway and 3) to understand p53 signaling pathway and its relation with Rho proteins in AML. In the long term, this study will collaborate with the development of more effective strategies for the treatment of patients with AML with or without TP53 mutation. (AU)

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