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In vivo leukemogenic potential of the mutant CD2-CRE/IL7R

Grant number: 17/10653-2
Support type:Scholarships abroad - Research Internship - Master's degree
Effective date (Start): August 21, 2017
Effective date (End): February 20, 2018
Field of knowledge:Biological Sciences - Immunology - Immunogenetics
Principal Investigator:José Andrés Yunes
Grantee:Mayara Ferreira Euzébio
Supervisor abroad: João 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:16/07724-2 - In vivo leukemogenic potential of the mutant IL-7R., BP.MS

Abstract

Acute lymphoid leukemia (ALL) is a cancer derived from immature lymphoid precursors T (ALL-T) or B (ALL-B). Nine% of the T-ALL has a mutation at the interleukin 7 receptor (IL7R), which confer constitutive activation of the JAK-STAT and PIK3/AKT pathways and potentiates cell survival and proliferation. To study the leukemogenic potential of this mutation in vivo, the B6-IL7RCPT animal model was developed, which contains an inverted exon 6 with the IL7R mutation, flanked by LoxP and Lox511 sequences. The mutant allele is only activated in the presence of the Cre recombinase, which requires crossing this lineage with a strain expressing Cre. Cells containing the IL7RCPT floxed allele and expressing the Cre recombinase will undergo "activation" of the mutant IL7R gene through Cre mediated recombination. In the Master's project we crossed the B6-IL7RCPT and B6.Cg-Tg (Vav1-cre) A2Kio/J lines in which Cre transcription occurs at the beginning of hematopoietic stem cell differentiation. The Vav1-cre/IL7RCPT model presented leukemia formation, but CD19 + cells (B cells) and not T cells. Our collaborators in Portugal have been worked with the CD2-cre model, in which the recombinase is expressed in precursors already compromised with The T-or B-lymphoid lineage. The CD2-Cre/IL7RCPT model also showed the appearance of B-derived leukemia (B-derived ALL) in animals, but with a higher penetrance than the Vav1-cre model. The appearance of B-ALL derived is not expected but is very interesting because IL7R-activating mutations were found in B-LLA derived from the BCR/ABL1-like subgroup, which is a more aggressive subtype. The aim of the present study is to characterize in vitro immunophenotype, signaling and signal transduction of the main associated pathways, transplantation and in vivo progression of a large number of leukemia developed by CD2-Cre/IL7RCPT animals, which has a greater penetrance than Vav1-cre. Given the importance of IL7R in the development of lymphocytes, there are other groups working with similar animal models. We want to join forces with our collaborators in Portugal (FAPESP-FCT project) to characterize for the first time the cellular and genomic bases of the development of one of the subtypes of ALL with a poor prognosis. (AU)