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.

Nucleophosmin leukemogenic mutant activates Wnt signaling during zebrafish development / E. Barbieri, G. Deflorian, F. Pezzimenti, D. Valli, M. Saia, N. Meani, A.M. Gruszka, M. Alcalay. - In: ONCOTARGET. - ISSN 1949-2553. - 7:34(2016 Jul), pp. 55302-55312. [10.18632/oncotarget.10878]

Nucleophosmin leukemogenic mutant activates Wnt signaling during zebrafish development

D. Valli;M. Saia;M. Alcalay
Ultimo
2016-07

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.
acute myeloid leukemia; nucleophosmin; zebrafish; primitive hematopoiesis; Wnt signaling
Settore MED/04 - Patologia Generale
Settore MED/03 - Genetica Medica
Settore MED/15 - Malattie del Sangue
28-lug-2016
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/426520
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