Veronika Janečková

Novel complex mutation in NPM1 gene in patient with acute myeloid leukemia

Somatic heterozygous mutations of the nucleophosmin gene (NPM1) are the most frequent mutations in acute myeloid leukemia (AML) patients. Mutations occur in approximately one-third of all adult patients with AML and in one half of cytogenetically normal AML patients (CN-AML). Mutations are mostly insertions that cluster within exon 11 – at the level of transcript (Ensembl transcript ref ENST00000296930, 1758 base pairs [bp]) it means within exon 12 – at the level of genomic DNA (Ensembl gene ref ENSG00000181163, NCBI Gene ref 4869 related to the Ensembl transcript ref ENST00000517671, 1338 bp). Frame shift mutations of the NPM1 gene cause the elongation of nucleophosmin phosphoprotein and its aberrant cytoplasmic expression.

The influence of mutational status and biological characteristics of acute myeloid leukemia on xenotransplantation outcomes in NOD SCID gamma mice

PurposeThis study aimed at analyzing the association of gene mutations and other acute myeloid leukemia (AML) characteristics with engraftment outcomes in immunodeficient mice and to select the engraftment outcomes that best reflect patient survival.MethodsMutations in 19 genes as well as leukemia- and patient-related characteristics were analyzed for a group of 47 de novo AML samples with respect to three engraftment outcomes: engraftment ability, engraftment intensity (percentage of hCD45+ cells) and engraftment latency. Leukemia-related characteristics were additionally analyzed in an extended group of 68 samples that included the 47 de novo samples, and additional 21 samples from refractory and relapsed cases. Engraftment outcomes were compared with overall and event-free survival of the patients.ResultsFor the 47 de novo samples, no single mutation influenced engraftment, whereas the NPM1mut/DNMT3Amut co-mutation was associated with higher engraftment ability. NPM1mut/FLT3-ITDneg had lower engraftment intensity. Among leukemia-related characteristics, a complex karyotype was associated with higher engraftment intensity. Among patient-related characteristics, higher cytogenetic risk was associated with higher engraftment intensity, and failure to achieve clinical remission was associated with shorter engraftment latency. In the extended group of 68 samples, white blood count was associated with higher engraftment ability, and the presence of a complex karyotype was associated with higher engraftment intensity. Association with patient overall survival was seen only for engraftment intensity.ConclusionsThe engraftment of AML was influenced by mutation-interactions and other AML characteristics, rather than by single mutated genes, and engraftment intensity best reflected clinical penetrance of AML.