Two Novel Mutations of the NPM1 Gene in Syrian Adult Patients with Acute Myeloid Leukemia and Normal Karyotype.

Ismael Alarbeed,Bassel Al-Halabi,Faten Moassass,Abdulsamad Wafa,Walid Alachkar,Imad Aboukhamis

doi:10.31557/apjcp.2021.22.1.227

Abstract

Objective:Somatic mutations in exon 12 of the NPM1 gene is one of the most common genetic abnormalities in adult acute myeloid leukemia (AML), which is observed in 25-35% of AML patients and in 50-60% of patients with cytogenetically normal AML (CN-AML). Methods:We performed Sanger sequencing of exon 12 of the NPM1 gene, on 44 CN-AML patients to characterize NPM1 status. Results:In this study, NPM1 mutations were identified in 10 (22.7%) of the 44 CN-AML patients. Among the 10 patients with NPM1 mutations, type A NPM1 mutations were identified in 8 (80%) patients, whereas non-A type NPM1 mutations were observed in 2 (20%) patients. Two non-A type NPM1 mutations were not previously reported: c.867-868InsCGGA and c.861-862InsTGCA. These two novel mutant proteins display a nuclear export signal (NES) motif (L-xxx-L-xx-V-x-L) less frequently and L-x-Lx-V-xx-V-x-L it has been never seen before, yet. However, both novel mutations show a tryptophan loss at codon 288 and 290 at the mutant C-terminus which are crucial for aberrant nuclear export of NPM into the cytoplasm. Conclusions:This study suggests previously unreported NPM1 mutations may be non-rare and thus additional sequence analysis is needed along with conventional targeted mutational analysis to detect non type-A NPM1 mutations.

Highlights

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy, which is characterized by uncontrolled proliferation of hematopoietic stem cells resulting in abnormal accumulation of myeloblasts
Somatic mutations in exon 12 of the NPM1 gene is one of the most common genetic abnormalities in adult acute myeloid leukemia (AML), which is observed in 25-35% of AML patients and in 50-60% of patients with cytogenetically normal AML (CN-AML)
Two non-A type NPM1 mutations were not previously reported: c.867-868InsCGGA and c.861-862InsTGCA. These two novel mutant proteins display a nuclear export signal (NES) motif (L-xxx-L-xx-V-x-L) less frequently and L-x-Lx-V-xx-Vx-L it has been never seen before, yet. Both novel mutations show a tryptophan loss at codon 288 and 290 at the mutant C-terminus which are crucial for aberrant nuclear export of NPM into the cytoplasm

Summary

Introduction

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy, which is characterized by uncontrolled proliferation of hematopoietic stem cells resulting in abnormal accumulation of myeloblasts. As far as cytogenetic abnormalities are concerned, the prognosis of AML patients was categorized into three risk groups: good, intermediate, and poor (Grimwade et al, 1998). The most common mutation in NPM1 patients is type A, which duplicates a TCTG tetranucleotide in the reference sequence at 956-959 and it accounts for up to 80% of adult AML with NPM1 mutations (Koh et al, 2009). Several studies have suggested that non- A type NPM1 mutations may function as prognostic factors for poor clinical outcomes (Koh et al, 2009; Park et al, 2012). We evaluated for the first mutational spectrum of NPM1 mutations in adult CN-AML Syrian patients newly diagnosed, which was directly sequenced. The biological and clinical features and the prognostic significance were assessed

Materials and Methods

Results

Discussion