Significance of NPM1 Gene Mutations in AML

Abstract

The aim of this literature review is to examine the significance of the nucleophosmin 1 (NPM1) gene in acute myeloid leukaemia (AML). This will include analysis of the structure and normal cellular function of NPM1, the type of mutations commonly witnessed in NPM1, and the mechanism by which this influences the development and progression of AML. The importance of NPM1 mutation on prognosis and the treatment options available to patients will also be reviewed along with current guidelines recommending the rapid return of NPM1 mutational screening results and the importance of employing a suitable laboratory assay to achieve this. Finally, future developments in the field including research into new therapies targeting NPM1 mutated AML are considered.

Keywords: AML; DNMT3A; FLT3; NPM1; fragment analysis.

Figure 1

Nucleophosmin 1 protein structure showing the nuclear export signal (NES) in the N-terminus domain, the nuclear localisation signal (NLS) of the central domain and the nucleolar localisation signal (NoLS) in the C-terminus domain containing tryptophan at amino acid positions 288 and 290 [17].

Figure 2

NPM1 exon 12 mutations. Mutation types (A-H) differ in the composition and number of nucleotides inserted (shown in red). All mutants shown have the same 4 amino acid addition at the end and an alteration to at least one of the tryptophans at positions 288 and 290 [42].

Figure 3

Model showing progression of clonal haematopoiesis to AML. Clonal haematopoiesis is believed to exist prior to AML development with mutations in DNMT3A often present. The acquisition of an NPM1 mutation is considered a driver mutation resulting in transformation to AML with further mutations in FLT3-ITD driving proliferation and establishing a predominant clone [20].

Figure 4

NPM1 detection using fragment analysis by capillary electrophoresis. The image on the left shows wild type NPM1 with the x-axis representing number of base pairs (bp) and the y-axis fluorescence. The image on the right shows the presence of a peak at 169 bp representing the wild type peak and the peak to the right at 173 bp showing the mutated NPM1 with a common 4 bp insertion. The area underneath each curve can be used to quantify the amount of wild type and mutant NPM1 present [87].