Ann Lab Med.  2013 Jan;33(1):60-64. 10.3343/alm.2013.33.1.60.

Identification of Two Novel NPM1 Mutations in Patients with Acute Myeloid Leukemia

• Jeon Y
• Seo SW
• Park S
• Park S
• Kim SY
• Ra EK
• Park SS
• Seong MW

• KMID: 1781299
• DOI: http://doi.org/10.3343/alm.2013.33.1.60

Abstract

BACKGROUND
Genetic abnormalities in adult AML are caused most frequently by somatic mutations in exon 12 of the NPM1 gene, which is observed in approximately 35% of AML patients and up to 60% of patients with cytogenetically normal AML (CN-AML).
METHODS
We performed mutational analysis, including fragment analysis and direct sequencing of exon 12 of the NPM1 gene, on 83 AML patients to characterize the NPM1 mutations completely.
RESULTS
In this study, NPM1 mutations were identified in 19 (22.9%) of the 83 AML patients and in 12 (42.9%) of the 28 CN-AML patients. Among the 19 patients with NPM1 mutations, type A NPM1 mutations were identified in 16 (84.2%) patients, whereas non-A type NPM1 mutations were observed in 3 (15.8%) patients. Two of the 3 non-A type NPM1 mutations were novel: c.867_868insAAAC and c.869_873indelCTTTAGCCC. These 2 novel mutant proteins display a nuclear export signal motif (L-xxx-L-xx-V-x-L) less frequently and exhibit a mutation at tryptophan 290 that disrupts the nucleolar localization signal.
CONCLUSIONS
This study suggests that novel NPM1 mutations may be non-rare and that supplementary sequence analysis is needed along with conventional targeted mutational analysis to detect non-A types of NPM1 mutations.

Keyword

NPM1; Nucleophosmin; AML

MeSH Terms

Adolescent
Adult
Aged
Aged, 80 and over
Amino Acid Motifs
Base Sequence
DNA Mutational Analysis
Exons
Female
Humans
Leukemia, Myeloid, Acute/*genetics/pathology
Male
Middle Aged
Mutation
Nuclear Proteins/*genetics
Young Adult
Nuclear Proteins

Figure

• 

  Fig. 1 Sequence analysis of the 2 novel NPM1 mutations. (A) c.867_868insAAAC, (B) c.869_873indelCTTTAGCCC, and (C) the wild-type NPM1 sequence.

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  Fig. 2 Nucleotide and amino acid sequences of the 2 novel NPM1 mutations. Wild type, type A (c.860_863dupTCTG), and type B mutations (c.863_864insCATG) are presented here. Tryptophans 288 and 290 (yellow background) are replaced by another amino acid in mutations A and B, whereas tryptophan 288 is retained in the 2 novel mutations identified in this study. The latter part of hydrophobic residue-rich NES motif (green background) is common to all types of mutation.Abbreviations: NES, nuclear export signal; NLS, nucleolar localization signal.

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