Oncotarget

Research Papers:

Analysis of NPM1 splice variants reveals differential expression patterns of prognostic value in acute myeloid leukemia

Malgorzata Zajac, Anna Dolnik, Grazyna Stasiak, Joanna Zaleska, Michal Kielbus, Jakub Czapinski, Matthias Schunn, Stephany C. Correa, Eliza Glodkowska-Mrowka, Reddy Chakkarappan Sundaram, Olga Jankowska-Lecka, Richard F. Schlenk, Hartmut Döhner, Konstanze Döhner, Andrzej Stepulak, Lars Bullinger and Krzysztof Giannopoulos _

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Oncotarget. 2017; 8:95163-95175. https://doi.org/10.18632/oncotarget.19871

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Abstract

Malgorzata Zajac1,*, Anna Dolnik2,*, Grazyna Stasiak1, Joanna Zaleska1, Michal Kielbus3, Jakub Czapinski3,4, Matthias Schunn2, Stephany C. Correa2,5, Eliza Glodkowska-Mrowka2,6,7, Reddy Chakkarappan Sundaram2, Olga Jankowska-Lecka8, Richard F. Schlenk2, Hartmut Döhner2, Konstanze Döhner2, Andrzej Stepulak3, Lars Bullinger2 and Krzysztof Giannopoulos1,9

1Department of Experimental Hematooncology, Medical University of Lublin, Lublin, Poland

2Department of Internal Medicine III, University of Ulm, Ulm, Germany

3Department of Biochemistry and Molecular Biology, Medical University of Lublin, Lublin, Poland

4Postgraduate School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland

5Stem-Cell Laboratory, Bone Marrow Transplantation Unit, National Cancer Institute (INCA), Rio de Janeiro, Brazil

6Department of Immunology, Medical University of Warsaw, Warsaw, Poland

7Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Medical University of Warsaw, Warsaw, Poland

8Department of Hematooncology and Bone Marrow Transplantation Unit, Medical University of Lublin, Lublin, Poland

9Department of Hematology, St. John’s Cancer Center, Lublin, Poland

*These authors have contributed equally to this work

Correspondence to:

Krzysztof Giannopoulos, email: krzysztof.giannopoulos@gmail.com

Lars Bullinger, email: lars.bullinger@uniklinik-ulm.de

Keywords: AML; splicing variants; NPM1

Received: October 24, 2016    Accepted: July 18, 2017    Published: August 03, 2017

ABSTRACT

Mutations of the nucleophosmin-1 (NPM1) gene in cytogenetically normal (CN) acute myeloid leukemia (AML) identify a group of patients with more favorable prognosis. NPM1 encodes three main alternatively spliced isoforms R1(B23.1), R2(B23.2), and R3(B23.3). The expression of splice variants R1, R2 and R3 were higher in AML patients compared to normal cells of healthy volunteers (HVs), although RNA-seq analysis revealed enhanced R2 expression also in less differentiated cells of HVs as well as in AML cells. The variant R2, which lacks exons 11 and 12 coding for the nucleolar localization domain, might behave similar to the mutant form of NPM1 (NPM1mut). In accordance, in CN-AML high R2 expression was associated with favorable impact on outcome. Moreover, functional studies showed nucleolar localization of the eGFP-NPM1 wildtype and cytoplasmic localization of the eGFP-NPM1 mut protein. While the eGFP-NPM1 R2 splice variant localized predominantly in the nucleoplasm, we also could detect cytoplasmic expression for the R2 variant. These results support a unique biological consequence of R2 overexpression and in part explain our clinical observation, where that high R2 variant expression was associated with a better prognosis in CN-AML patients.


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