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Molecular genetic analisys of c-Kiт gene mutations in acute myeloid leukemia in the age aspect

[Experimental medicine]
Alexander Vladimirovich Vinogradov; Denis Vladimirovich Izotov; Alexey Vasilievich Rezaykin; Sergey Vladimirovich Sazonov; Evgeny Shchetinin; Dmitry Bobryshev; Alexander Grigorievich Sergeev;

Direct automatic sequencing was used to study the oncogenic potential of mutations of the c-Kit gene in exons 7–12 and 16–19 of the gene in 67 patients with newly identified forms of acute myeloid leukemia (AML). Besides, 56 samples were additionally tested for insertion in exon 12 of the NPM1 gene using molecular genetic and immunohistochemical methods. The frequency of functionally significant mutations in the c-Kit gene was 13.4 % (n=9), 5 of which were in the group of AML patients aged 15–45 years (15.2 %), 4 – in elderly patients (11.8 %). That is, the frequency of mutations of the c-Kit gene in patients, depending on age, did not differ statistically significantly. Three samples revealed insertions in the NPM1 gene (5.4 %). However, by computer modeling using Protein Homology/AnalogY Recognition Engine, it was shown that only the missense mutation of с. 2447 A>T, as well as insertions and deletions of exons 10 and 11 (6.0 %, n=4) had oncogenic potential among the detected molecular changes. At the same time, the most common non-synonymous transversion of c. 1621 A>C (7.5 %, n=5), both isolated and combined with the transit of c. 1636 A>G, did not have any significant effect on the structure and did not lead to spontaneous activation of the c-Kit protein. The prognostic impact of detected mutations in the c-Kit gene in AML was unfavorable, but the use of tyrosine kinase inhibitors has clinical prospects along with high-dose chemotherapy and allogeneic bone marrow transplantation.

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Keywords: acute myeloid leukemia, c-Kit gene, young age, old and senile age, sequencing, protein structure modeling


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