Analysis of NPM1 Gene Mutations in Chinese Adults with Acute Myeloid Leukemia.

Many European groups have described that mutations at exon-12 of the nucleophosmin (NPM1) gene are the most frequent genetic lesion in acute myeloid leukemia (AML) (45.7%~61.7% of all adult AMLs with normal karyotype). This outstanding discovery provides a promising minimal residual disease (MRD) marker for AMLs with normal karyotype. To clarify the prevalence and the clinical profile of NPM1 mutations in Chinese patients with AML, we analyzed a cohort of 156 newly diagnosed adult AMLs for this mutation. Genomic DNAs were prepared from bone marrow samples of these patients. NPM1 exon 12 mutations were detected using direct sequencing or fragment analysis of DNA-PCR products. NPM1 mutations were present in 28.2% of the overall population, including 1/1(100%) of M0, 11/27(40.7%) of M1, 11/46(23.9%) of M2, 0/29(0%) of M3, 2/9(22.2%) of M4, 18/39(46.2%) of M5 and 1/5(20.0%) of M6. NPM1 gene mutations were more prevalent in patients with a normal karyotype (37 of 90; 41.1%), when compared with patients with karyotypic abnormalities (7 of 66; 10.6%; P<0.001). Sequence analysis of 25 NPM1 mutated cases revealed known mutations (type A, B, NM, and PM) as well as 1 novel sequence variation (here named as type S). All mutational types were heterozygous and showed a 4 bp insertion between position nucleotide 960 and 961 (Genebank accession number: NM-002500). NPM1 mutations were significantly associated with old age (P<0.05), high peripheral white cell count (P<0.05) and FAB-M1/M5, but negatively associated with expression of CD34 (P<0.05) and CD117 (P<0.05). In conclusion, NPM1 mutations also represent a common genetic abnormality in Chinese adults with AML, especially in the presence of a normal karyotype. The occurrence of NPM1 mutations indicates an age-dependent characteristic. NPM1 mutated cases show a special clinical subtype of AML. Further studies are urgently needed to confirm the role of NPM1 mutations in leukemogenesis. The altered nucleo-cytoplasmic transport of NPM1 mutated protein is probably a potential therapic target for AML with NPM1 mutations.