Molecular modeling of mutant FLT3 in acute myeloid leukemia patients aged 15-45 and 60-75 years old
Aim: to estimate the functional implications of mutations in FLT3 gene in acute myeloid leukemia (AML) patients (pts) aged 15-45 and 60-75 years old using Protein Homology/AnalogY Recognition Engine. Materials and methods. Bone marrow and peripheral blood samples obtained from 70 AML pts (including 32 aged 15 to 45 and 38 aged 60 to 75 years old), treated in Sverdlovsk Regional Hematological Centre during the period 2009-2017. Distribution of the pts according to classification was as follows: AML M0 - 3, M1 - 6, M2 - 30, М3 - 4, M4 - 18, M4eo - 2, M5 - 3, M6 - 1, acute myelofibrosis - 1, blastic plasmacytoid dendritic cell neoplasm - 1. Detection of mutations in FLT3 gene performed by automatic direct sequencing technique. Sequencing realized using automatic genetic analyzers ABI Prism 310 (Applied Biosystems, USA) and 3130 Genetic Analyzer (Thermo Fisher Scientific Inc., USA). Results. The average frequency of prognostic significant mutations in FLT3 gene among the treated AML pts was 20.0%, including 7 cases (21.9%) in young pts and 7 cases (18.4%) in old pts. Functional implications of mutations in FLT3 gene confirmed using Protein Homology/AnalogY Recognition Engine. The mechanism of the mutation effect of mutations on the structure and functional properties of the protein Flt3 due to violations autoinhibitory conformation of the molecule with subsequent ligand-independent activation of the catalytic domains. Therefore, mutation status of the FLT3 gene should be considered for the development of personalized programs for the treatment of AML, including the use of tyrosinekinase inhibitors of types I and II, determining the medical indications for high-dose polychemotherapy, bone marrow transplantation and palliative treatment.