Research Papers:

Nucleophosmin leukemogenic mutant activates Wnt signaling during zebrafish development

Elisa Barbieri, Gianluca Deflorian, Federica Pezzimenti, Debora Valli, Marco Saia, Natalia Meani, Alicja M. Gruszka and Myriam Alcalay _

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Oncotarget. 2016; 7:55302-55312. https://doi.org/10.18632/oncotarget.10878

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Elisa Barbieri1,4, Gianluca Deflorian2, Federica Pezzimenti2, Debora Valli1, Marco Saia1, Natalia Meani1, Alicja M. Gruszka1,*, Myriam Alcalay1,3,*

1Department of Experimental Oncology, Istituto Europeo di Oncologia, Milan, Italy

2The FIRC Institute of Molecular Oncology (IFOM) Foundation, Milan, Italy

3Dipartimento di Oncologia ed Emato-Oncologia, Università degli Studi di Milano, Milan, Italy

4Current address: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, USA

*These authors contributed equally to this work

Correspondence to:

Myriam Alcalay, email: [email protected]

Keywords: acute myeloid leukemia, nucleophosmin, zebrafish, primitive hematopoiesis, Wnt signaling

Received: September 17, 2015     Accepted: June 26, 2016     Published: July 28, 2016


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.

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PII: 10878