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Deciphering the relation between Rho subfamily of GTPases and p53-mediated signaling pathway in acute Myeloid leukemia

Grant number: 21/14630-2
Support Opportunities:Regular Research Grants
Duration: August 01, 2022 - April 30, 2023
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Mariana Lazarini
Grantee:Mariana Lazarini
Host Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil


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 explore the relation between the p53 signaling pathway and Rho proteins in AML. To this end, the effects of RhoA, RhoB or RhoC knockdown will be investigated in the activation of the p53 signaling pathway, and in the proliferation, apoptosis and DNA damage responses of myeloid cell lines with wild type or mutated TP53. 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 to the elucidation of 1) RhoA, RhoB and RhoC functions in central cellular properties for leukemia development mediated by p53 and 2) the regulation 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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