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Mutation landscape of acute myeloid leukemia in elderly patients

Genes & Cells: Vol XIV, №4, 2019, pp: 19-24 DOI: 10.23868/201912027

Authors

A.V. Vinogradov, A.V. Rezaykin, S.V. Sazonov, A.G. Sergeev, М.Y. Kapitonova

The molecular genetic landscape of acute myeloid leukemia (AML) have specific features in elderly patients, and these features correlates with hematopoietic progenitor cells senescence. Aim: to estimate the frequency of mutations in DNMT3A, FLT3, KIT, NPM1, NRAS, TP53 and WT1 genes in AML patients in elderly. Bone marrow and peripheral blood samples obtained from 54 AML patients aged over 60 years old. Distribution of the patients according to FAB-classification was as follows: AML M0 — 2, M1 — 6, M2 — 27, М3 — 2, M4 — 11, M5 — 1, M6 — 3, acute myelofibrosis — 1, blastic plasmacytoid dendritic cell neoplasm — 1. Detection of mutations in DNMT3A, FLT3, KIT, NPM1, NRAS, TP53 and WT1 genes performed by automatic direct sequencing technique. In the study group were more common patients with unfavorable (33.3%, n=18) and unspecified (42.6%, n=23) cytogenetics. The average frequency of functionally significant mutations in all investigated genes among the treated AML patients was 38.9% (n=21), including 3 cases (27.3%) with normal karyotype, 11 cases (61.1%) with unfavorable cytogenetics, 7 cases (30.4%) with unspecified karyotype. Average frequency of mutations in TP53 gene exons 4–11 was 20.0%, FLT3 gene exons 12–15 and 19–21 18.4%, DNMT3A exons 18–26 — 9.1%, NRAS gene exons 1–4 — 7.7%, KIT gene exons 7–12 and 16–19 — 5.9%, NPM1 gene exons 9–12 — 5.4% (n=2), DNMT3A — 9.1% (n=1). Multiple point mutations in investigated genes were detected in 11.1% AML specimens (n=6, usually FLT3 gene mutations, including FLT3 ITD in 4 cases). Additional gene mutations detection using direct sequencing allowed to clarify the prognostic stratification of AML from groups of unspecified and intermediate prognosis in 35.9% (n=10). In all cases, they were associated with an unfavorable prognosis. Thus, using of cytogenetic and additional molecular genetic research, a favorable prognosis of overall survival was established in 2 cases (3.7%), intermediate — in 9 cases (16.7%), unfavorable — in 27 cases (50.0%), and unspecified — in 16 (29.6%).

Keywords: acute myeloid leukemia, elderly, DNMT3A gene, FLT3 gene, KIT gene, NPM1 gene, NRAS gene, TP53 gene, WT1 gene, sequencing.

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