Molecular and epigenetic analysis in JAK2 V617F-positive and -negative chronic myeloproliferative neoplasms

• Grant number: 11/20135-2
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2012
• End date: April 30, 2014
• Field of knowledge: Health Sciences - Medicine - Pathological Anatomy and Clinical Pathology
• Principal Investigator: Fabíola Attié de Castro
• Grantee: Fabíola Attié de Castro
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Polycythemia Vera (PV), Essential Thrombocytosis (ET), and Primary Myelofibrosis (PMF) are Ph-negative chronic myeloproliferative neoplasms characterized by the either the presence of progenitors independence or by hypersensitive to numerous cytokines associated with cell differentiation and intense proliferation. The cellular and molecular mechanisms involved in the pathogenesis and progression of these neoplasms have not been fully elucidated and therefore only a few diagnostic and prognostic markers have been described. The contribution of the V617F JAK mutation to the clinical laboratory features of PV has been described, however this mutation partly explains the myeloproliferation and myeloaccumulation verified both in ET and PMF. Since only about 50% of ET and PMF patients present the JAK2 V617F mutation, we hypothesize that cell proliferation and apoptosis deregulation, mutations in the MPL gene TET2 and epigenetic abnormalities also contribute to the pathogenesis of these diseases. The present project aims to describe potential alterations in the molecules involved in regulation of apoptosis and cell cycle control, in the JAK/STAT pathway and methylation profile, mainly in V617F JAK2 negative patients. Specifically this study aims to evaluate in PV, ET and PMF: 1) the protein expression using reverse protein arrays; 2) the methylation profile of genes related to apoptosis and cell cycle (qPCR Array System); 3) the presence of MPL and JAK2 (12 of 14 exon) mutations. Another experimental approach constitutes to verify if constitutive kinase activity of JAK2 induces epigenetic alterations in genes relates to apoptosis and cell cycle. In this case, this cell lineage will be treated either with the inhibitor, or with classic apoptogenic agents that act in the TRAIL death receptor pathway, and treated cells will be evaluated for their susceptibility to apoptosis, and the patterns of protein expression and epigenetic profile. Overall, this study will provide a description of new therapeutic targets and the role of epigenetic and molecular alterations in the pathogenesis of these diseases in patients positive and negative for JAK2 mutation. (AU)

Scientific publications

(4)

(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)

BERZOTI-COELHO, MARIA GABRIELA; FERREIRA, ALINE FERNANDA; NUNES, NATALIA DE SOUZA; PINTO, MARIANA TOMAZINI; ROCHA JUNIOR, MAUR-CIO CRISTIANO; SIMOES, BELINDA PINTO; MARTINEZ-A, CARLOS; SOUTO, ELIZABETH XISTO; PANEPUCCI, RODRIGO ALEXANDRE; COVAS, DIMAS TADEU; et al. The expression of Death Inducer-Obliterator (DIDO) variants in Myeloproliferative Neoplasms. BLOOD CELLS MOLECULES AND DISEASES, v. 59, p. 25-30, JUL 2016. (11/20135-2)

FERREIRA, A. F.; MOURA, L. G.; TOJAL, I.; AMBROSIO, L.; PINTO-SIMOES, B.; HAMERSCHLAK, N.; CALIN, G. A.; IVAN, C.; COVAS, D. T.; KASHIMA, S.; et al. ApoptomiRs expression modulated by BCR-ABL is linked to CML progression and imatinib resistance. BLOOD CELLS MOLECULES AND DISEASES, v. 53, n. 1-2, p. 47-55, JUN-AUG 2014. (11/20135-2)

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, AUG 2020. (11/51616-6, 11/20135-2)

TOGNON-RIBEIRO, R.; NUNES, N.; MOURA, L.; SOUZA, M.; SOUTO, E.; PALMA, L.; SIMOES, B.; CHAUFFAILLE, M.; CASTRO, F.. APOPTOSIS-RELATED GENES METHYLATION PROFILE IS ALTERED IN MYELOPROLIFERATIVE NEOPLASMS PHILADELPHIA NEGATIVE PATIENTS. Haematologica, v. 98, p. 1-pg., 2013-06-12. (11/20135-2, 11/51616-6)