Regulators microRNAs of HIPPO pathway in Chronic Myeloid Leukemia

• Grant number: 15/23555-3
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: July 01, 2016
• End date: February 29, 2020
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Fabíola Attié de Castro
• Grantee: Maria Gabriela Berzoti Coelho
• Host 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

Abstract

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

(6)

(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; COMINAL, JUCARA GASTALDI; PEREIRA, LUIZ MIGUEL; BERZOTI-COELHO, MARIA GABRIELA; BERBEL, GIOVANA MICHELASSI; BARONI, LUCIANA; MALTA, TATHIANE; TOGNON, RAQUEL; NUNES, NATALIA DE SOUZA; SOUTO, ELIZABETH XISTO; et al. Hippo pathway-related genes expression is deregulated in myeloproliferative neoplasms. MEDICAL ONCOLOGY, v. 39, n. 5, p. 11-pg., 2022-05-01. (13/08135-2, 14/50947-7, 15/23555-3, 18/19714-7, 15/21866-1, 14/04234-9)

COMINAL, JUCARA GASTALDI; CACEMIRO, MAIRA DA COSTA; BERZOTI-COELHO, MARIA GABRIELA; PEREIRA, ILLY ENNE GOMES; FRANTZ, FABIANI GAI; SOUTO, ELIZABETH XISTO; COVAS, DIMAS TADEU; FIGUEIREDO-PONTES, LORENA LOBO DE; OLIVEIRA, MARIA CAROLINA; MALMEGRIM, KELEN CRISTINA RIBEIRO; et al. Bone Marrow Soluble Mediator Signatures of Patients With Philadelphia Chromosome-Negative Myeloproliferative Neoplasms. FRONTIERS IN ONCOLOGY, v. 11, MAY 18 2021. (13/08135-2, 14/50947-7, 18/01756-5, 18/19714-7, 15/23555-3)

CACEMIRO, MAIRA DA COSTA; COMINAL, JUCARA GASTALDI; BERZOTI-COELHO, MARIA GABRIELA; TOGNON, RAQUEL; NUNES, NATALIA DE SOUZA; SIMOES, BELINDA; PEREIRA, ITALO SOUSA; CARLOS, DANIELA; FACCIOLI, LUCIA HELENA; DE FIGUEIREDO-PONTES, LORENA LOBO; et al. Differential cytokine network profile in polycythemia vera and secondary polycythemia. SCIENTIFIC REPORTS, v. 10, n. 1, APR 27 2020. (15/23555-3, 17/23501-6, 18/01756-5, 14/50947-7, 18/19714-7, 13/08135-2)

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. (15/23555-3, 15/25637-7, 11/23236-4)

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. (15/25637-7, 15/23555-3, 14/04234-9)

DE ALMEIDA, FELIPE CAMPOS; BERZOTI-COELHO, MARIA G.; TORO, DIANA MOTA; CACEMIRO, MAIRA DA COSTA; BASSAN, VITOR LEONARDO; BARRETTO, GABRIEL DESSOTTI; MARQUES GARIBALDI, PEDRO MANOEL; PALMA, LEONARDO CARVALHO; DE FIGUEIREDO-PONTES, LORENA LOBO; SORGI, CARLOS ARTERIO; et al. Bioactive Lipids as Chronic Myeloid Leukemia's Potential Biomarkers for Disease Progression and Response to Tyrosine Kinase Inhibitors. FRONTIERS IN IMMUNOLOGY, v. 13, p. 8-pg., 2022-04-13. (14/50947-7, 15/21866-1, 18/19714-7, 15/23555-3, 15/00658-1, 13/08135-2, 18/01756-5)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

COELHO, Maria Gabriela Berzoti. Deregulation of microRNAs expression and its role in Bcr-Abl+ cells resistance to TKI therapy. 2020. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC) Ribeirão Preto.