Elisa Barbieri

First name
Elisa
Last name
Barbieri
Year of Study
Thesis Title
Modulation of stem cell signalling pathways by nucleophosmin and its leukemogenic mutant
Thesis Abstract
About one third of acute myeloid leukemias (AML) is characterized by the aberrant cytoplasmic localization of nucleophosmin (NPM1), a ubiquitously expressed phosphoprotein that acts as a molecular chaperone and shuttles between nucleus and cytoplasm. Although several animal models have been generated to unravel the mechanism of action of the cytoplasmic mutant NPMc+, it remains poorly understood. We identified a novel function of both wild type NPM1 and NPMc+ in the modulation of Wnt signaling during zebrafish development and primitive hematopoiesis. The injection of NPMc+ and human NPM1 mRNAs in one cell stage zebrafish embryos reveals an opposite effect of the two proteins in the modulation of the Wnt signaling: NPM1 can inhibit the pathways whereas the mutant can activate it. Furthermore, NPM1 and NPMc+ have an opposite effect on the expression of dkk1b, a well known inhibitor of the Wnt pathway, and the co-injection of NPM1 and NPMc+ mRNA rescues the phenotype, suggesting a dominant negative effect of the mutant on the wild-type. Through whole mount in situ hybridization, markers of hematopoiesis have been studied revealing that the myeloproliferative effect of NPMc+ can be overcome by the co-injection of dkk1b, suggesting that the mutant can act by activating the pathway. Taken together, data presented in this thesis suggest that NPMc+ can activate Wnt signaling and that the pathway may be involved in the mechanism of NPMc+ AML establishment and/or progression.
Students representatives
Off
Curricula Term