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Identification of mutations functionally associated with the mutant IL7Ra in T-ALL

Grant number: 12/10284-3
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): July 01, 2012
Effective date (End): May 31, 2017
Field of knowledge:Biological Sciences - Genetics
Principal Investigator:José Andrés Yunes
Grantee:Gisele Olinto Libanio Rodrigues
Home Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil
Associated scholarship(s):15/21149-8 - Functional identification of genes associated with mutant IL7Ra in T-ALL, BE.EP.DR

Abstract

Acute lymphoblastic leukemia of T cells (T-ALL) is a malignancy derived from transformation of precursors linfoblásticos the thymus and represents 10-15% of cases of childhood ALL. The patient with T-ALL tends to present itself to the diagnosis with a very high score of circulating blasts, mediastinal mass and central nervous system involvement. The prognosis of children and adolescents with T-ALL has improved greatly in recent years due to intensified therapies. However some cases still fall during treatment or within the first two years after treatment of the disease and will eventually died. Methodological advances have allowed greater understanding of the genetic alterations underlying the T-ALL. The IL7/IL7R mediated signaling is essential for normal development and homeostasis of precursors of T cells In recent work our research group showed that the blasts of patients with T-ALL have mutations in the alpha chain of the IL7 receptor (IL-7Ra), leading to constitutive activation of this protein and consequently the uncontrolled proliferation of these cells. Some genetic changes are important factors to initiate leukemia, but in many cases these changes are insufficient to form a full leukemic phenotype, suggesting the occurrence of oncogenic mutations collaborative. One way to identify possible mutations collaborative is to verify the association among the different mutations in different patients. In our study, mutations of IL7R shown to be associated with alterations in genes Hoxa. Another study shows association with IL7R mutations of GATA3 mutations in the chimeric transcript and the presence of SET-NUP214. This project will validate and seek other mutation(s) that potentially collaborate with IL7Rmut to leukemia phenotype. To do this proceed sequencing the genome of five T-ALL samples with mutated IL7R the Centro Infantil Boldrini. GATA3 mutations in transcribed SET-NUP214 and other mutations result of our genomic sequencing cloned into viral vectors are used to transduce and, together with the mutant IL7R, D1 and BAF3 cells for analysis of viability / cell proliferation in medium without cytokines IL3 and IL7, respectively. D1 cells also transduced will be injected into immunosuppressed animals RAG1-/ - to evaluate the progression in vivo testing different combinations of genes with mutant IL7R.

Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
RODRIGUES, Gisele Olinto Libanio. Identification of mutations functionally associated with IL7R'alpha' mutant in T-ALL. 2017. Doctoral Thesis - Universidade Estadual de Campinas, Instituto de Biologia.

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