Analysis of NPM1 splice variants reveals differential expression patterns of prognostic value in acute myeloid leukemia
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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
Krzysztof Giannopoulos, email: [email protected]
Lars Bullinger, email: [email protected]
Keywords: AML; splicing variants; NPM1
Received: October 24, 2016 Accepted: July 18, 2017 Published: August 03, 2017
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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