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

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.