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Consequence of G372v and T454M mutations in SF1 functionality

Grant number: 19/04487-8
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): April 01, 2019
Effective date (End): August 31, 2019
Field of knowledge:Biological Sciences - Biochemistry - Molecular Biology
Principal Investigator:Leticia Fröhlich Archangelo
Grantee:Vivian Maura Gregoracci
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:14/01458-3 - Defining the functional role of the splicing factor regulator (KIS) during leukemogenesis using a murine bone marrow transplantion model, AP.JP


The SF1 protein recognizes the 3' regions of the introns during the initial stages in the formation of the spliceosome, but it is not necessary for the constitutive splicing of all premRNA in the cells. Thus, SF1 acts as an alternative splicing factor on a sub-set of cellular premRNAs. Somatic mutations in several genes related to the splicing process, including SF1 and SF3b, have recently been described in hematologic diseases, consolidating defects in the splicing machinery as a new mechanism in leukemogenesis. In a study published by Yoshida and collaborators, SF1 was found mutated in a small subset of patients, of which 1.3% were myelodysplastic syndromes (SMD), 0.7% of new acute myeloid leukemia (AML) and 1.9% of myeloproliferative neoplasms (PMN) (Yoshida et al. 2011). In another study, the authors identified SF1 mutations among 0.6% of patients with DMS (Haferlach et al. 2013). The functional consequence of these mutations has been our object of study. The SF1, G372V and T454M mutations described by Yoshida and collaborators (2011) were selected for the study by our group. In order to investigate the consequence of the presence of G372V and T454M mutations in the normal function of SF1, our group generated constructions of retroviral vectors (MIG-SF1_WT, MIG-SF1_G372V, MIG-SF1_T454M and empty MIG vector) that were used to transduce cells of leukemic lineage Namalwa and U937, which started to express the constructions in a stable manner. As an objective of this work plan, we intend to use the leukemic lineages that express the mutated SF1 proteins and evaluate them for viability, clonogenic and proliferative capacity in relation to the cells that express wild SF1.

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