Молекулярно-генетическая характеристика ОМЛ с t(8;21) у детей

Статья в Elpub

Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2018; 17: 9-15

Молекулярно-генетическая характеристика ОМЛ с t(8;21) у детей

Панферова А.В. , Гаськова М.В. , Зеркаленкова Е.А. , Апрелова Е.В. , Казакова А.Н. , Тимофеева Н.М. , Солдаткина О.И. , Никитин Е.Н. , Чекменева Ю.Ю. , Калинина И.И. , Плясунова С.А. , Ольшанская Ю.В. , Новичкова Г.А. , Масчан М.А. , Масчан А.А.

https://doi.org/10.24287/1726-1708-2018-17-1-9-15

Аннотация

Подгруппу острых миелобластных лейкозов (ОМЛ) с хромосомными перестройками t(8;21)(q22;q22) и inv(16)(p13q22)/t(16;16)(p13;q22) обозначают как CBF-ОМЛ (от англ. core binding factor - острый миелоидный лейкоз). Эта клинически и биологически гетерогенная группа имеет относительно хороший прогноз, тем не менее в 40% случаев происходят рецидивы заболевания. Известно, что экспрессия RUNX1-RUNX1T1 и CBFB-MYH11 химерных протеинов недостаточна для индуцирования лейкоза, по этой причине CBF-ОМЛ считают классической моделью патогенеза в результате кооперации нескольких событий. Для того чтобы охарактеризовать наиболее полный спектр мутаций у 30 пациентов с t(8;21)-ОМЛ, мы выполнили высокопроизводительное секвенирование 54 генов. Показано, что молекулярный профиль детских ОМЛ с t(8;21) высоко гетерогенен и имеет 60% мутаций в генах KIT, FLT3 и N/KRAS, активирующих внутриклеточные сигнальные пути с участием тирозинкиназ. Варианты мутаций встречаются с разными долями мутантного аллеля. Мутации в генах, ответственных за эпигенетическую регуляцию (ASXL1, KDM6A, EZH2, BCORL1, BCOR, TET2, IDH1, IDH2), и в генах когезинового комплекса (RAD21, SMC1A, SMC3, STAG2) выявлены также с высокой частотой - 43%. Таким образом, полученные данные поддерживают теорию функционального взаимодействия нескольких мутаций и влияния такой кооперации на патофизиологию ОМЛ с t(8;21), отражая уникальный патогенез в данной подгруппе. Применение современных технологий, таких как метод высокопроизводительного секвенирования, целесообразно для диагностики детских ОМЛ.

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Pediatric Hematology/Oncology and Immunopathology. 2018; 17: 9-15

Molecular characterization of pediatric acute myeloid leukemia with t(8;21)

Panfyorova A. V., Gaskova M. V., Zerkalenkova E. A., Aprelova E. V., Kazakova A. N., Timofeeva N. M., Soldatkina O. I., Nikitin E. N., Chekmeneva Y. Y., Kalinina I. I., Plyasunova S. A., Olshanskaya Y. V., Novichkova G. A., Maschan M. A., Maschan A. A.

https://doi.org/10.24287/1726-1708-2018-17-1-9-15

Abstract

Acute myeloid leukemia (AML) with t(8;21) or inv(16) have been considered as unique group within AML and are usually reported as core binding factor AML (CBF-AML) but there is significant clinical and biological heterogeneity within and relapse incidence reaches up to 40%. It is known that, translocations involving CBFs are not sufficient to induce fulminant leukemia alone, therefore is considered as a model for the multistep pathogenesis of AML. To characterize more broad spectrum of genetic changes we performed extensive mutational analysis of 54 genes by high-throughput sequencing in 30 patients with t(8;21)-AML. The molecular landscape of pediatric AML with t(8;21) was highly heterogeneous and harbored frequent mutations in genes activating tyrosine kinase signaling (including KIT, N/KRAS, and FLT3) – 60% in group with variable mutant allele ratios. Mutations in genes that regulate chromatin conformation or encode members of the cohesin complex were observed with high frequencies – 43% as well. These data support the theory of synergic cooperation between these events and suggest that diverse cooperating mutations may influence CBF-AML pathophysiology as well as clinical behavior and point to potential unique pathogenesis of t(8;21). The adoption of advances in DNA sequencing as a high-throughput sequencing technology is a useful tool in diagnostics of pediatric AML.

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