трансгенные животные

Модели миелофиброза (обзор литературы и собственные данные)

МИЕЛОИДНЫЕ ОПУХОЛИ , ,

А.А. Силютина, И.И. Гин, Н.М. Матюхина, Е.Н. Балаян, П.А. Бутылин

ФГБУ «Северо-Западный федеральный медицинский исследовательский центр им. В.А. Алмазова» Минздрава России, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341

Для переписки: Павел Андреевич Бутылин, канд. биол. наук, ул. Аккуратова, д. 2, Санкт-Петербург, Российская Федерация, 197341; e-mail: butylinp@gmail.com

Для цитирования: Силютина А.А., Гин И.И., Матюхина Н.М. и др. Модели миелофиброза (обзор литературы и собственные данные). Клиническая онкогематология. 2017;10(1):75–84.

DOI: 10.21320/2500-2139-2017-10-1-75-84

РЕФЕРАТ

Актуальность и цели. Развитие хронических миелопролиферативных заболеваний проходит длительный латентный период, затрудняя исследования механизмов патогенеза. Наблюдения, отмеченные в клинической практике, зачастую требуют экспериментальной проверки. Механизмы онкологической трансформации, связанные с возникновением мутаций, встречающихся при хронических миелопролиферативных заболеваниях, были подтверждены на моделях трансгенных животных. Биологические модели позволили выявить комплексную природу развития миелофиброза. Однако изучение отдельных клеточных механизмов требует создания новых моделей. В работе представлен как обзор опубликованных моделей развития миелопролиферативных заболеваний, в основном первичного миелофиброза, так и результаты исследования разработанной клеточной линии с экспрессией JAK2 V617F. Цель настоящей работы — создание клеточной линии с экспрессией трансформирующей мутации JAK2 V617F в клетках острого моноцитарного лейкоза THP-1.

Методы. Основой для создания трансгенной клеточной линии послужила линия клеток моноцитарного лейкоза THP-1, способная дифференцироваться в макрофаги. Мутация V617F была получена методом направленного мутагенеза. Было создано две трансгенных линии: одна с экспрессией гена JAK2 с мутацией V617F, другая — JAK2 дикого типа.

Результаты. Обе трансгенные линии характеризовались повышенной экспрессией JAK2 по сравнению с немодифицированными клетками. При рутинном культивировании трансгенные THP-1 сохраняли морфологию моноцитов. После обработки форболовым эфиром THP-1 дифференцировались в макрофаги и прикреплялись к культуральному пластику. Адгезировавшие клетки принимали различную форму: часть отличалась сферической формой, у других отмечены псевдоподии. Значимых различий по доле жизнеспособных клеток не наблюдалось. Однако макрофаги с экспрессией мутантного гена JAK2 и JAK2 дикого типа имели тенденцию к уменьшению количества нежизнеспособных клеток при культивировании.

Заключение. Полученная клеточная модель может служить объектом для оценки влияния мутации JAK2 V617F на про- и антифибротический потенциал макрофагов, что может пролить свет на патогенетическую роль макрофагов в развитии миелофибороза. Кроме того, с помощью данной модели можно исследовать новые методы терапии и диагностики как первичного, так и вторичного миелофиброза.

Ключевые слова: Ph-негативные хронические миелопролиферативные заболевания, первичный миелофиброз, JAK2 V617F, трансгенные животные.

Получено: 15 сентября 2016 г.

Принято в печать: 13 декабря 2016 г.

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