MOLECULAR MODELING OF MUTANT FLT3 IN ACUTE MYELOID LEUKEMIA PATIENTS AGED 15-45 AND 60-75 YEARS OLD
DOI: 10.22138/2500-0918-2018-15-3-384-392
A.V. Vinogradov, D.V. Izotov, A.V. Rezaykin, S.V. Sazonov, A.G. Sergeev, S.L. Leontiev
Ural State Medical University, Yekaterinburg, Russian Federation;
Sverdlovsk Regional Clinical Hospital N1, Yekaterinburg, Russian Federation;
Institute Medical Cells Technology, Yekaterinburg, Russian Federation
Abstract. 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.
Keywords: mutation, acute myeloid leukemia, FLT3 gene, direct sequencing, Protein Homology/AnalogY Recognition Engine
Received 19.04.2018
For citation:
Vinogradov A.V., Izotov D.V., Rezaykin A.V., Sazonov S.V., Sergeev A.G., Leontiev S.L. Molecular modeling of mutant FLT3 in acute myeloid leukemia patients aged 15-45 and 60-75 years old. Vestn. Ural. Med. Akad. Nauki. = Journal of Ural Medical Academic Science. 2018, Vol. 15, no. 3, pp. 384–392. DOI: 10.22138/2500-0918-2018-15-3-384-392 (In Russ)
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Authors
Alexander V. Vinogradov
Sverdlovsk Regional Hospital №1
Cand.Sci. (Med.), Chief Therapist
Russian Federation, 620014, Yekaterinburg, Weiner str., 34b
a.vinogradov@egov66.ru
Denis V. Izotov
Ural State Medical University
Intern
Russian Federation, 620028, Yekaterinburg, Repin str., 3
phoenus@yandex.ru
Alexey V. Rezaykin
Ural State Medical University, Department of Microbiology, Virology and Immunology, Laboratory of Molecular Diagnostic
Cand.Sci. (Med.), Professor Assistant
Russian Federation, 620028, Yekaterinburg, Repin str., 3
alexrez@usma.ru
Sergey V. Sazonov
Ural State Medical University, Department of Histology, Cytology and Embryology, Institute of Medical Cell Technologies
Dr. Sci. (Med.), Professor, Chief of the Department
Russian Federation, 620028, Yekaterinburg, Repin str., 3
sazonov@usma.ru
Alexander G. Sergeev
Ural State Medical University, Department of Microbiology, Virology and Immunology, Laboratory of Molecular Diagnostic
Dr. Sci. (Med.), Professor, Chief of the Department, Scientific Chief of the Laboratory
Russian Federation, 620028, Yekaterinburg, Repin str., 3
sergeev@usma.ru
Sergey L. Leontiev
Institute of Medical Cell Technologies
Dr. Sci. (Med.), Professor, Head of Institute of Medical Cell Technologies
Russian Federation, 620137, Yekaterinburg, ul. Vilonova 76a
imct@celltechnologies.ru