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

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 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 exporti...

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Bibliographic Details
Published in:Genes 2021-09, Vol.12 (9), p.1426
Main Authors: Venanzi, Alessandra, Rossi, Roberta, Martino, Giovanni, Annibali, Ombretta, Avvisati, Giuseppe, Mameli, Maria Grazia, Sportoletti, Paolo, Tiacci, Enrico, Falini, Brunangelo, Martelli, Maria Paola
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus - genetics
Acute myeloid leukemia
Aged
Amino acid sequence
Animals
Antibodies
Antigens
Bone marrow
C-Terminus
Cells, Cultured
Cloning
Cytoplasm
Cytoplasm - metabolism
DNA polymerase
Gene deletion
Humans
Immunohistochemistry
Insertion
Leukemia
Leukemia, Myeloid, Acute - genetics
Leukemia, Myeloid, Acute - metabolism
Leukemia, Myeloid, Acute - pathology
Leukemogenesis
Localization
Male
Mice
Microscopy
Mutants
Mutation
Myeloid leukemia
NIH 3T3 Cells
Nuclear Export Signals - genetics
Nuclear transport
Nucleophosmin - chemistry
Nucleophosmin - genetics
Nucleophosmin - metabolism
Nucleotides
Patients
Phosphatase
Plasmids
Protein Transport - genetics
Proteins
Software
Terminal protein
Tumors
Western blotting
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Description
Summary: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 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 . Immunohistochemistry (IHC) detects cytoplasmic and is predictive of the molecular alteration. Besides IHC and molecular sequencing, Western blotting (WB) with anti- mutant specific antibodies is another approach to identify -mutated AML. Here, we show that among 382 AML cases with 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 as critical in AML leukemogenesis.
ISSN:2073-4425
2073-4425
DOI:10.3390/genes12091426