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Study of Rho function in DNA damage repair and migration of Acute Myeloid Leukemia cells and its association with p53 signaling pathway

Grant number: 22/07033-0
Support Opportunities:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): October 01, 2022
Effective date (End): September 30, 2026
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Mariana Lazarini
Grantee:Stephany Suelen de Castro Sampaio
Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

Acute Myeloid Leukemia (AML) is a severe hematologic malignancy characterized by blockage in myeloid differentiation and uncontrolled proliferation of leukemic cells that accumulate in the bone marrow and blood. The TP53 gene, known as "guardian of the genome" is an important tumor suppressor encoding the p53 protein, whose inactivation is related to increased proliferation, survival and migration of Cancer cells. Mutations in TP53 are found in 7-15% of patients with AML and indicate an unfavorable prognosis. Furthermore, most cases of AML may have loss of (non-mutational) p53 function by additional mechanisms. The Rho proteins GTPases of the Rho subfamily (RhoA, RhoB and RhoC) participate in several cellular processes, such as DNA damage repair and migration. These cellular functions are directly or indirectly controlled by the p53 signaling pathway, whose relationship with Rho proteins has been evidenced in recent studies. Results from our research group show Rho dysregulation in AML and association with prognosis. The objective of this project is to evaluate the participation of Rho in the processes of DNA damage repair and migration of AML cells. The potential association between p53 signaling pathway activation status and gene expression levels of RhoA, RhoB and RhoC will also be explored. For this, myeloid cell lines with presence (U937) or absence of TP53 mutation (OCI-AML3 and MOLM13) and laboratory techniques of gene silencing, western blot, PCR and assays using microscopy and flow cytometry will be used. Analyzes of patient samples will be performed using patient samples belonging to the biorepository. The generated results will contribute to the understanding of the functions of RhoA, RhoB and RhoC in AML and their relationship with the p53 signaling pathway. (AU)

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