title: Nucleophosmin leukemogenic mutant activates Wnt signaling during zebrafish development.
abstract: Nucleophosmin (NPM1) is a ubiquitous multifunctional phosphoprotein with both oncogenic and tumor suppressor functions. Mutations of the NPM1 gene are the most frequent genetic alterations in acute myeloid leukemia (AML) and result in the expression of a mutant protein with aberrant cytoplasmic localization, NPMc+. Although NPMc+ causes myeloproliferation and AML in animal models, its mechanism of action remains largely unknown. Here we report that NPMc+ activates canonical Wnt signaling during the early phases of zebrafish development and determines a Wnt-dependent increase in the number of progenitor cells during primitive hematopoiesis. Coherently, the canonical Wnt pathway is active in AML blasts bearing NPMc+ and depletion of the mutant protein in the patient derived OCI-AML3 cell line leads to a decrease in the levels of active β-catenin and of Wnt target genes. Our results reveal a novel function of NPMc+ and provide insight into the molecular pathogenesis of AML bearing NPM1 mutations.
authors.affiliation: Department of Experimental Oncology, Istituto Europeo di Oncologia, Milan, Italy.|Current address: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Barbieri
authors.affiliation: The FIRC Institute of Molecular Oncology (IFOM) Foundation, Milan, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Deflorian
authors.affiliation: The FIRC Institute of Molecular Oncology (IFOM) Foundation, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Pezzimenti
authors.affiliation: Department of Experimental Oncology, Istituto Europeo di Oncologia, Milan, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Valli
authors.affiliation: Department of Experimental Oncology, Istituto Europeo di Oncologia, Milan, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Saia
authors.affiliation: Department of Experimental Oncology, Istituto Europeo di Oncologia, Milan, Italy.
authors.forename: Natalia
authors.initials: N
authors.lastname: Meani
authors.affiliation: Department of Experimental Oncology, Istituto Europeo di Oncologia, Milan, Italy.
authors.forename: Alicja M
authors.initials: AM
authors.lastname: Gruszka
authors.affiliation: Department of Experimental Oncology, Istituto Europeo di Oncologia, Milan, Italy.|Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, Milan, Italy.
authors.forename: Myriam
authors.initials: M
authors.lastname: Alcalay
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000032:analysis; D006412:Hematopoietic Stem Cells / Q000502:physiology; D015470:Leukemia, Myeloid, Acute / Q000209:etiology / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D000090243:Nucleophosmin; D060449:Wnt Signaling Pathway / Q000502:physiology*; D015027:Zebrafish / Q000196:embryology*
chemical_list: C491761:AXIN2 protein, human; D060466:Axin Protein; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin
keywords: Wnt signaling; acute myeloid leukemia; nucleophosmin; primitive hematopoiesis; zebrafish