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Aberrant IL7R signaling in leukemogenesis: from the basics to potential therapeutics

Grant number: 14/20015-5
Support type:Regular Research Grants
Duration: August 01, 2015 - September 30, 2019
Field of knowledge:Health Sciences - Medicine
Cooperation agreement: Fundação para a Ciência e a Tecnologia (FCT)
Principal Investigator:José Andrés Yunes
Grantee:José Andrés Yunes
Principal investigator abroad: João Pedro Taborda Barata
Institution abroad: Universidade de Lisboa, Portugal
Home Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil
Assoc. researchers:Patricia Yoshioka Jotta ; Pedro Otavio de Campos Lima ; Priscila Pini Zenatti ; Silvia Regina Brandalise

Abstract

Acute lymphoblastic leukemia (ALL) is an aggressive cancer and the most frequent childhood malignancy, arising from clonal expansion of lymphoid progenitors arrested at different stages of development. Currently, more than 80% of children with ALL, either B or T, are alive and disease-free at 5 years. Remarkable success has been recently achieved with use of imatinib for the treatment of BCR-ABL1 positive ALL, providing a paradigm for new studies aiming at characterizing potentially actionable kinase-altering mutations in ALL. We and others have found that around 10% of T-ALL patients display gain-of-function oncogenic mutations in the IL7R gene. Recent analysis on the high risk Philadelphia-like B-ALL subtype revealed IL7R or other JAK-STAT-pathway activating mutations in 10% and 50% of cases, respectively. In this project we propose to make use of two different, complementary inducible knock-in mouse models of IL7R mutations, which are being generated independently by Dr. Yunes (Brazil) and Dr. Barata (Portugal), to characterize the impact of mutational activation of IL7R on T- and B-cell development and determine whether it has the ability to drive leukemogenesis per se or in cooperation with other oncogenic hits. In parallel, we will screen 3,700 lead molecules, enriched in signal transduction inhibitors, in order to validate new molecular targets and tools for pre-clinical intervention against aberrant IL-7R-mediated signaling in ALL. We expect not only to generate considerable knowledge about the mechanisms, pathways and cellular targets underlying IL7R-mediated transformation in vivo, but also hopefully fulfill our common goal of translating basic knowledge into valid and novel therapeutic tools that may help in ALL treatment. (AU)