Generating Zebrafish (Danio rerio) models to study the IL-7R gain of function during lymphopoiesis

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% of all cases of ALL in children and it is characterized by the uncontrolled expansion of T-cell lymphocytes. From the T-ALL cases described in the literature, 25% of them are involved with the IL-7R pathway. Gain-of-function mutations in IL-7R± were first described at the Boldrini Children`s Center in patients with T-ALL, wherein the most common mutations are those with cysteine insertions in the extracellular juxtamembrane region of IL-7R±, generating a constitutively active homodimer. In addition, patients with gain-of-function mutations in the receptor also had shown loss of function of WNT pathway. Recently, many ALL models have emerged using zebrafish, making it an important model for the study of cancer, mainly by the possibility of genetic manipulation and visualization of the biological process in vivo. In this project, we will generate zebrafish models to study the biological function of human IL-7R gain-of-function (hIL-7Rmut) during embryonic development and T cell differentiation. We will activate the mutant in early developmental embryos and in specific cell types (hematopoietic stem cells, T-cell progenitors and mature T-cells) and evaluate proliferation, cellular maturation and cellular dynamics of the hematopoietic cells, moreover, we will evaluate the tumorigenic potential of the mutant depending on the experimental approach. The aim of this project is to implement zebrafish models at the Boldrini Research Center for the study of embryonic development, hematopoiesis and childhood leukemia, areas not yet explored with this model in Brazil. The generation of models to study cancer will provide support for future research aimed at discovering new therapeutic targets to suppress carcinogenesis. (AU)