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Dissecting the RAS/MEK/ERK pathway downstream the oncogenic IL7R in acute lymphoblastic leukemia

Grant number: 20/11380-2
Support type:Scholarships abroad - Research Internship - Doctorate
Effective date (Start): December 01, 2020
Effective date (End): November 30, 2021
Field of knowledge:Health Sciences - Medicine
Principal Investigator:José Andrés Yunes
Grantee:Juliana Ronchi Corrêa
Supervisor abroad: Joao Pedro Taborda Barata
Home Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil
Local de pesquisa : Universidade de Lisboa, Portugal  
Associated to the scholarship:17/02400-7 - Development of an animal model of precursor B-cell acute lymphoblastic leukemia with the oncogenic IL7R mutation, BP.DR

Abstract

The oncogenic IL7R is known to activate three pathways in acute lymphoid leukemia (ALL): JAK/STAT, PI3K/AKT/mTOR and RAS/MEK/ERK. However, the activation of RAS/MEK/ERK has not been characterized. Mutations in RAS/MEK/ERK are recurrent in human ALL (7/15 cases of ALL with mutations in the IL7R have cooccurring mutations in genes of the RAS/MEK/ERK pathway) and in murine ALL originating from our mouse model of the oncogenic IL7R. Moreover, the combined use of RAS and PI3K inhibitors has a synergistic effect against ALL carrying IL7R or JAK mutations. This suggest a collaboration between the RAS/MEK/ERK with the JAK/STAT and/or PI3K/AKT/mTOR pathways for the development of ALL. In this project we aim to characterize the mechanism of activation of RAS/MEK/ERK by the oncogenic IL7R. Primary murine ALL samples from the oncogenic IL7R mouse model will be used to evaluate possible correlations between activation of the JAK/STAT, PI3K/AKT/mTOR and RAS/MEK/ERK pathways. Site directed mutagenesis of the IL7R receptor and co-immunoprecipitation assays will be used to dissect the participation of IL7R's residue Y449, JAK1, PI3K, and SHC in RAS activation by the oncogenic and wild type IL7R. Inhibitor of RAS/MEK/ERK will be tested in vivo against different murine ALLs, alone or in combination with other agents, to evaluate its potential use in ALL therapy.