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Molecular and epigenetic changes of apoptosis, cell cycle and JAK/STAT signaling pathway in JAK2 V617F-positive and negative chronic myeloproliferative neoplasms

Grant number: 11/51616-6
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): December 01, 2011
Effective date (End): October 17, 2013
Field of knowledge:Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
Principal Investigator:Fabíola Attié de Castro
Grantee:Raquel Tognon Ribeiro
Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


Chronic Myeloproliferative Neoplasms (cMPN) - Essential Thrombocythemia (ET), Primary Myelofibrosis (PMF) and Polycythemia Vera (PV) - are clonal hematopoietic stem cell malignancies characterized by an accumulation of mature myeloid cells in bone marrow and peripheral blood. Despite the advances in the molecular knowledge, the physiopathology of these diseases remains unknown. It is clear that the JAK2 V617F mutation has a key role in PV; however, this mutation is only partially responsible for the myeloproliferation and myeloaccumulation in ET and PMF. Taking into account that only about 50% of ET and PMF patients harbor the JAK2 V617F mutation, we hypothesize that deregulated apoptosis processes, other mutations (e.g. in the MPL or TET2 genes), as well as epigenetic modifications contribute to the physiopathology of these diseases. Therefore, in order to elucidate the alterations in apoptosis regulation, cell cycle and epigenetic modifications in these patients, mainly in JAK2 V617F negative ones, this project aims to analyze the protein expression (Reverse Protein Array), evaluate the methyl profile of genes related to apoptosis and cell cycle (qPCR Array System), and detect mutations in JAK2 éxon 12 and exon 14, as well in MPL gene in PV, ET and PMF patients. Furthermore, the SET-2 cell line (JAK2V617F-positive) and JAK2 inhibitors will be employed to verify if the epigenetic modification profile is linked to the JAK2 activity and if combination of these inhibitors with classical apoptosis-inducers or stimulation of the death receptor apoptosis pathway (by TRAIL) are able to overcome resistance to cell death of JAK2 V617F-positive cells. (AU)

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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)
TOGNON, RAQUEL; ALMEIDA-E-SILVA, DANILLO C.; ANDRAOS-REY, RITA; RISTOV, MITKO; AMBROSIO, LUCIANA; DE ALMEIDA, FELIPE CAMPOS; DE SOUZA NUNES, NATALIA; XISTO SOUTO, ELIZABETH; DE LOURDES PEROBELLI, LEILA; SIMOES, BELINDA PINTO; et al. A proteomic study of myeloproliferative neoplasms using reverse-phase protein arrays. Leukemia & Lymphoma, v. 61, n. 13, . (11/51616-6, 11/20135-2)

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