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Regulators microRNAs of Hippo pathway in chronic myeloid leukemia

Grant number: 15/23555-3
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): July 01, 2016
Effective date (End): July 31, 2020
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Fabíola Attié de Castro
Grantee:Maria Gabriela Berzoti Coelho
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated scholarship(s):17/23501-6 - CDR1as' role in tumorigenesis and metastasis of melanoma by miR-7 regulation, BE.EP.DR


Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome (Ph), which gives rise to the BCR-ABL1 gene. The BCR-ABL1 oncogene encodes the Bcr-Abl protein with constitutive activity of tyrosine kinase (TK), which is responsible for clinical and laboratory evidence of the disease. The TK inhibitors (TKIs) used in the CML treatment are capable of inducing molecular and cytogenetic remissions in patients, but the resistance to this therapy has been described. Despite all the knowledge of the pathogenesis and progression of CML and resistance of patients to TKIs treatment, not all cellular and molecular mechanisms involved in these processes were fully elucidated. In this context, this project will evaluate potential miRNAs that regulate HIPPO pathway in CML. The HIPPO signaling pathway was defined as tumor suppressor, responsible for regulating processes as proliferation, differentiation and cell death and the deregulation of its function is related to the tumorigenesis process. Thus, we will explore the possible relationship between microRNAs and deregulation of HIPPO pathway in chronic myeloid leukemia through the study of microRNAs expression that targets regulatory molecules of this signaling pathway. MicroRNAs (miRNAs) are small endogenous RNAs that regulate gene expression. The aberrant expression of specific miRNAs have been associated to the pathogenesis of several hematological malignancies such as chronic lymphocytic leukemia, myeloproliferative neoplasms, myelodisplastic syndromes and lymphomas. Therefore, will be quantified the expression levels of microRNAs miR-125a, miR-31, miR-373, miR-125-b, miR-141, miR-129-5p, miR-132, miR-506, miR-375, miR-125a-5p and miR-135b and the protein expression of targets of these miRNAs that are involved in the HIPPO signaling pathway in cells from CML patients in different phases of disease, who are sensitive or resistant to imatinib mesylate (IM) and also in Bcr-Abl positive cell lines sensitive or resistant to IM. The results may contribute to description of new therapeutic targets, biomarkers and also to increase the efficacy of TKI therapy in CML.

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CACEMIRO, MAIRA DA COSTA; BERZOTI-COELHO, MARIA GABRIELA; COMINAL, JUCARA GASTALDI; BURIN, SANDRA MARA; DE CASTRO, FABIOLA ATTIE. Hippo pathway deregulation: implications in the pathogenesis of haematological malignancies. Journal of Clinical Pathology, v. 70, n. 1, p. 9-14, JAN 2017. Web of Science Citations: 0.
BURIN, SANDRA MARA; BERZOTI-COELHO, MARIA GABRIELA; COMINAL, JUCARA GASTALDI; AMBROSIO, LUCIANA; TORQUETI, MARIA REGINA; SAMPAIO, SUELY VILELA; DE CASTRO, FABIOLA ATTIE. The L-amino acid oxidase from Calloselasma rhodostoma snake venom modulates apoptomiRs expression in Bcr-Abl-positive cell lines. Toxicon, v. 120, p. 9-14, SEP 15 2016. Web of Science Citations: 10.

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