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Study of CALR del52 and ins5 knock-in mouse models and comparison to the JAK2V617F knock-in mouse model

Grant number: 16/03265-3
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): July 01, 2016
Effective date (End): March 31, 2017
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Fabíola Attié de Castro
Grantee:Maira da Costa Cacemiro
Supervisor abroad: William Vainchenker
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Local de pesquisa : Institut National de la Santé et de la Recherche Médicale (Inserm), France  
Associated to the scholarship:14/04234-9 - Expression of molecules of HIPPO/LATS pathway in chronic neoplasms myeloproliferative, BP.DR

Abstract

Myeloproliferative neoplasms (MPN) are haematological disorders characterized by increased proliferation and accumulation of mature myeloid cells of one or more of the myeloid series (granulocytic, erythroid or megakaryocytic). Among the MPN are polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Patients with these disorders may present the JAK2V617F mutation which occurs in 95% of cases of PV and 50% of cases of ET and PMF. Recently a new mutation has been associated to MPN, this mutation occur on Calreticulin gene (CALR) and is present in 60 to 84% of MPN samples with non-mutated JAK2 and MPL corresponding to approximately 20%-30% of ET and PMF, but are generally absent in PV. Two main types of this mutation has been associate to MNP, a 52pb deletion (del 52, type I) (53%) and a 5bp insertion (ins5, type II) (32%). In a previous study with a knock-in model induced by viral plasmid for both Del52 and Ins5 showed that CALR mutants are able and sufficient to induce a thrombocytosis through MPL activation. Besides, CALR ins5 and del52 CALR displayed a different efficiency for the development of myelofibrosis, rapid for del52 and with no progression or very long latency for ins5. Thus, the retroviral mouse model mimicked the natural history of MPN patients and underlined the correlation between genotype and phenotype of the disease[7]. Therefore, the aim of this project is to evaluate the role of CALR mutation on hematopoesis. for that will be analyzed by flow cytometer the phenotypic characteristic (Lin- / Sca-1 + / c-kit + / CD150 + / CD48- ) of hematopoetic stem cells (HSC), analyzed by measuring blood and marrow parameters, perfomed clonogenic assays and carry out secondary or tertiary transplants. Moreover, analyzed signaling pathway by mass cytometer CyTOF (CEA, Fontenay-aux-Roses), and finally study if IFNa can also target cells carrying the mutation CALR focusing on HSC compartment and by which mechanism. (AU)

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)
MAIRA DA COSTA CACEMIRO; JUÇARA GASTALDI COMINAL; RAQUEL TOGNON; NATALIA DE SOUZA NUNES; BELINDA PINTO SIMÕES; LORENA LÔBO DE FIGUEIREDO-PONTES; LUIZ FERNANDO BAZZO CATTO; FABÍOLA TRAINA; ELIZABETH XISTO SOUTO; FABIANA ALBANI ZAMBUZI; FABIANI GAI FRANTZ; FABÍOLA ATTIÉ DE CASTRO. Philadelphia-negative myeloproliferative neoplasms as disorders marked by cytokine modulation. Hematology, Transfusion and Cell Therapy, v. 40, n. 2, p. -, Jun. 2018.

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