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A Curious Novel Combination of Nucleophosmin (NPM1) Gene Mutations Leading to Aberrant Cytoplasmic Dislocation of NPM1 in Acute Myeloid Leukemia (AML)

Nucleophosmin (NPM1) mutations occurring in acute myeloid leukemia (AML) (about 50 so far identified) cluster almost exclusively in exon 12 and lead to common changes at the NPM1 mutants C-terminus, i.e., loss of tryptophans 288 and 290 (or 290 alone) and creation of a new nuclear export signal (NES...

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Autores principales: Venanzi, Alessandra, Rossi, Roberta, Martino, Giovanni, Annibali, Ombretta, Avvisati, Giuseppe, Mameli, Maria Grazia, Sportoletti, Paolo, Tiacci, Enrico, Falini, Brunangelo, Martelli, Maria Paola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468273/
https://www.ncbi.nlm.nih.gov/pubmed/34573408
http://dx.doi.org/10.3390/genes12091426
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author Venanzi, Alessandra
Rossi, Roberta
Martino, Giovanni
Annibali, Ombretta
Avvisati, Giuseppe
Mameli, Maria Grazia
Sportoletti, Paolo
Tiacci, Enrico
Falini, Brunangelo
Martelli, Maria Paola
author_facet Venanzi, Alessandra
Rossi, Roberta
Martino, Giovanni
Annibali, Ombretta
Avvisati, Giuseppe
Mameli, Maria Grazia
Sportoletti, Paolo
Tiacci, Enrico
Falini, Brunangelo
Martelli, Maria Paola
author_sort Venanzi, Alessandra
collection PubMed
description Nucleophosmin (NPM1) mutations occurring in acute myeloid leukemia (AML) (about 50 so far identified) cluster almost exclusively in exon 12 and lead to common changes at the NPM1 mutants C-terminus, i.e., loss of tryptophans 288 and 290 (or 290 alone) and creation of a new nuclear export signal (NES), at the bases of exportin-1(XPO1)-mediated aberrant cytoplasmic NPM1. Immunohistochemistry (IHC) detects cytoplasmic NPM1 and is predictive of the molecular alteration. Besides IHC and molecular sequencing, Western blotting (WB) with anti-NPM1 mutant specific antibodies is another approach to identify NPM1-mutated AML. Here, we show that among 382 AML cases with NPM1 exon 12 mutations, one was not recognized by WB, and describe the discovery of a novel combination of two mutations involving exon 12. This appeared as a conventional mutation A with the known TCTG nucleotides insertion/duplication accompanied by a second event (i.e., an 8-nucleotide deletion occurring 15 nucleotides downstream of the TCTG insertion), resulting in a new C-terminal protein sequence. Strikingly, the sequence included a functional NES ensuring cytoplasmic relocation of the new mutant supporting the role of cytoplasmic NPM1 as critical in AML leukemogenesis.
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spelling pubmed-84682732021-09-27 A Curious Novel Combination of Nucleophosmin (NPM1) Gene Mutations Leading to Aberrant Cytoplasmic Dislocation of NPM1 in Acute Myeloid Leukemia (AML) Venanzi, Alessandra Rossi, Roberta Martino, Giovanni Annibali, Ombretta Avvisati, Giuseppe Mameli, Maria Grazia Sportoletti, Paolo Tiacci, Enrico Falini, Brunangelo Martelli, Maria Paola Genes (Basel) Article Nucleophosmin (NPM1) mutations occurring in acute myeloid leukemia (AML) (about 50 so far identified) cluster almost exclusively in exon 12 and lead to common changes at the NPM1 mutants C-terminus, i.e., loss of tryptophans 288 and 290 (or 290 alone) and creation of a new nuclear export signal (NES), at the bases of exportin-1(XPO1)-mediated aberrant cytoplasmic NPM1. Immunohistochemistry (IHC) detects cytoplasmic NPM1 and is predictive of the molecular alteration. Besides IHC and molecular sequencing, Western blotting (WB) with anti-NPM1 mutant specific antibodies is another approach to identify NPM1-mutated AML. Here, we show that among 382 AML cases with NPM1 exon 12 mutations, one was not recognized by WB, and describe the discovery of a novel combination of two mutations involving exon 12. This appeared as a conventional mutation A with the known TCTG nucleotides insertion/duplication accompanied by a second event (i.e., an 8-nucleotide deletion occurring 15 nucleotides downstream of the TCTG insertion), resulting in a new C-terminal protein sequence. Strikingly, the sequence included a functional NES ensuring cytoplasmic relocation of the new mutant supporting the role of cytoplasmic NPM1 as critical in AML leukemogenesis. MDPI 2021-09-16 /pmc/articles/PMC8468273/ /pubmed/34573408 http://dx.doi.org/10.3390/genes12091426 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Venanzi, Alessandra
Rossi, Roberta
Martino, Giovanni
Annibali, Ombretta
Avvisati, Giuseppe
Mameli, Maria Grazia
Sportoletti, Paolo
Tiacci, Enrico
Falini, Brunangelo
Martelli, Maria Paola
A Curious Novel Combination of Nucleophosmin (NPM1) Gene Mutations Leading to Aberrant Cytoplasmic Dislocation of NPM1 in Acute Myeloid Leukemia (AML)
title A Curious Novel Combination of Nucleophosmin (NPM1) Gene Mutations Leading to Aberrant Cytoplasmic Dislocation of NPM1 in Acute Myeloid Leukemia (AML)
title_full A Curious Novel Combination of Nucleophosmin (NPM1) Gene Mutations Leading to Aberrant Cytoplasmic Dislocation of NPM1 in Acute Myeloid Leukemia (AML)
title_fullStr A Curious Novel Combination of Nucleophosmin (NPM1) Gene Mutations Leading to Aberrant Cytoplasmic Dislocation of NPM1 in Acute Myeloid Leukemia (AML)
title_full_unstemmed A Curious Novel Combination of Nucleophosmin (NPM1) Gene Mutations Leading to Aberrant Cytoplasmic Dislocation of NPM1 in Acute Myeloid Leukemia (AML)
title_short A Curious Novel Combination of Nucleophosmin (NPM1) Gene Mutations Leading to Aberrant Cytoplasmic Dislocation of NPM1 in Acute Myeloid Leukemia (AML)
title_sort curious novel combination of nucleophosmin (npm1) gene mutations leading to aberrant cytoplasmic dislocation of npm1 in acute myeloid leukemia (aml)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468273/
https://www.ncbi.nlm.nih.gov/pubmed/34573408
http://dx.doi.org/10.3390/genes12091426
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