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In vivo leukemogenic potential of the mutant IL-7R.

Grant number: 16/07724-2
Support type:Scholarships in Brazil - Master
Effective date (Start): August 01, 2016
Effective date (End): July 31, 2019
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:José Andrés Yunes
Grantee:Mayara Ferreira Euzébio
Home Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil
Associated scholarship(s):17/10653-2 - In vivo leukemogenic potential of the mutant CD2-CRE/IL7R, BE.EP.MS

Abstract

The acute lymphoblastic leucemia (ALL) is an aggressive cancer characterized by the overproduction and accumulation of immature lymphoid precursors, which proliferate and replace normal hematopoietic cells in the bone marrow. ALL can be an acute lymphoblastic leukemia T (T-ALL) or acute lymphoblastic leukemia B (B-ALL). Approximately 35% of ALL cases are associated with the presence of chromosome translocations, affecting the expression of important genes in the development of T cells. Besides that, several mutations have been described in genes of lymphoid development regulation, cellular cycle, tumor suppressor and signal transduction. Mutations in the IL7R gene have been found in T-ALL cases as well in a subtype of poor prognostic B-ALL. Our research group found recently a gain-of-function mutation in the IL7R gene, present in 9% of T-ALL cases. The mutations confer constitutive activation of JAK-STAT and PI3K/AKT pathways. Cells transduced with the mutant IL7R shown increased in vitro survival and proliferation, and growth factors independence. When transplanted into mouse, these cells developed tumors and infiltrated into secondary organs. To evaluate if the IL7R mutation is enough to promote leukemia development, our research group development a B6-Il7rCPT conditional knock-in mouse, which contains an inverted exon 6 with the IL7R mutation, flanked by LoxP and Lox511 sequences. In this project we plan to breed B6-Il7rCPT mice with the B6.Cg-Tg(Vav1-cre)A2Kio/J strain. The Vav1 promoter directs the expression of Cre in hematopoietic stem cells, therefore activating the conditional mutant IL7R allele. The aim of this study is to evaluate the leukemogenic potential of the mutant IL7R, determining the type and differentiation stage of the produced leukemia.