Novel NPM1 exon 5 mutations and gene fusions leading to aberrant cytoplasmic nucleophosmin in AML

Author:

Martelli Maria Paola12ORCID,Rossi Roberta1,Venanzi Alessandra1,Meggendorfer Manja3,Perriello Vincenzo Maria1,Martino Giovanni1ORCID,Spinelli Orietta4ORCID,Ciurnelli Raffaella2,Varasano Emanuela1,Brunetti Lorenzo12ORCID,Ascani Stefano1,Quadalti Corinne1,Cardinali Valeria12,Mezzasoma Federica1ORCID,Gionfriddo Ilaria1ORCID,Milano Francesca1,Pacini Roberta2,Tabarrini Alessia2,Bigerna Barbara2,Albano Francesco5ORCID,Specchia Giorgina5,Vetro Calogero6ORCID,Di Raimondo Francesco6,Annibali Ombretta7ORCID,Avvisati Giuseppe7,Rambaldi Alessandro4ORCID,Falzetti Franca12,Tiacci Enrico12,Sportoletti Paolo12,Haferlach Torsten3,Haferlach Claudia3,Falini Brunangelo12ORCID

Affiliation:

1. Hematology, Centro di Ricerche Emato-Oncologiche, University of Perugia, Perugia, Italy;

2. Santa Maria della Misericordia Hospital of Perugia, Perugia, Italy;

3. Munich Leukemia Laboratory, Munich, Germany;

4. Hematology, ASST Papa Giovanni XXIII, University of Milan, Bergamo, Italy;

5. Hematology, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy;

6. Division of Hematology, Azienda Ospedaliero Universitaria Policlinico-San Marco, Catania, Italy; and

7. Hematology, Campus Bio-medico, University of Rome, Rome, Italy

Abstract

Abstract Nucleophosmin (NPM1) mutations in acute myeloid leukemia (AML) affect exon 12, but also sporadically affect exons 9 and 11, causing changes at the protein C-terminal end (tryptophan loss, nuclear export signal [NES] motif creation) that lead to aberrant cytoplasmic NPM1 (NPM1c+), detectable by immunohistochemistry. Combining immunohistochemistry and molecular analyses in 929 patients with AML, we found non–exon 12 NPM1 mutations in 5 (1.3%) of 387 NPM1c+ cases. Besides mutations in exons 9 (n = 1) and 11 (n = 1), novel exon 5 mutations were discovered (n = 3). Another exon 5 mutation was identified in an additional 141 patients with AML selected for wild-type NPM1 exon 12. Three NPM1 rearrangements (NPM1/RPP30, NPM1/SETBP1, NPM1/CCDC28A) were detected and characterized among 13 979 AML samples screened by cytogenetic/fluorescence in situ hybridization and RNA sequencing. Functional studies demonstrated that in AML cases, new NPM1 proteins harbored an efficient extra NES, either newly created or already present in the fusion partner, ensuring its cytoplasmic accumulation. Our findings support NPM1 cytoplasmic relocation as critical for leukemogenesis and reinforce the role of immunohistochemistry in predicting AML-associated NPM1 genetic lesions. This study highlights the need to develop new assays for molecular diagnosis and monitoring of NPM1-mutated AML.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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