Влияние квизартиниба на устойчивость клеток острого миелоидного лейкоза с FLT3‑ITD-позитивным и FLT3‑ITD-негативным фенотипом к TRAIL-индуцированному апоптозу

Аннотация

Внутренние тандемные дупликации в гене, кодирующем мембранный домен FLT3 (FLT3‐ITD), являются наиболее частым генетическим изменением и неблагоприятным прогностическим фактором у пациентов с острым миелоидным лейкозом (ОМЛ). Ингибиторы FLT3 нового поколения эффективно индуцируют гибель клеток ОМЛ с FLT3‐ITD-позитивным фенотипом (FLT3‐ITD(+)) и потенциально обладают цитотоксическим действием против клеток ОМЛ с FLT3‐ITD-негативным фенотипом (FLT3‐ITD(−)), но в больших концентрациях. Однако остается открытым вопрос о возможном влиянии ингибиторов FLT3 нового поколения на цитотоксическую активность молекулярных эффекторов противоопухолевого иммунитета, особенно в контексте гетерогенности первичного клонального состава ОМЛ, включающего как FLT3‐ITD(+)-, так и FLT3‐ITD(−)-клетки. В работе показано, что применение квизартиниба, ингибитора FLT3 нового поколения, повышало устойчивость FLT3‐ITD(−)-клеток ОМЛ, но не FLT3‐ITD(+)-клеток ОМЛ, к цитотоксическому действию ключевого молекулярного эффектора противоопухолевого иммунитета – цитокина Apo2L/TRAIL, за счет изменения экспрессии проапоптотических TRAIL-рецепторов, содержания белка cFLIP и экспрессии генов белков семейств IAP и BCL‑2. Кроме того, были идентифицированы индуцированные квизартинибом изменения внутриклеточных сигнальных путей, потенциально регулирующих TRAIL-резистентность клеток ОМЛ. Выявленные квизартиниб-индуцированные транскрипционные изменения представляют интерес не только в контексте комбинированной терапии с TRAIL, но и имеют более широкое значение для понимания механизмов лекарственной устойчивости клеток ОМЛ.

Сноски

* Адресат для корреспонденции.

Дополнительные материалы

Приложение

Вклад авторов

Р.С. Фадеев, М.И. Кобякова, Я.В. Ломовская – концепция и руководство работой; М.И. Кобякова, К.С. Краснов, И.В. Одинокова, Я.В. Ломовская, А.С. Сенотов, А.М. Ермаков, А.С. Диденко – проведение экспериментов; М.И. Кобякова, Я.В. Ломовская, Е.И. Мещерякова, И.С. Фадеева – обсуждение результатов исследования; М.И. Кобякова, Я.В. Ломовская – написание текста; Р.С. Фадеев – редактирование текста статьи.

Финансирование

Работа выполнена в рамках государственного задания № 075-00223-25‑03 и в рамках государственного задания ФНИ FWNR-2025‑0014.

Благодарности

В работе использовано оборудование Центра коллективного пользования «Структурно-функциональные исследования биосистем» ИТЭБ РАН (https://www.ckp-rf.ru/catalog/ckp/3037).

Конфликт интересов

Авторы заявляют об отсутствии конфликта интересов.

Соблюдение этических норм

Настоящая статья не содержит описания каких-либо исследований с участием людей или животных в качестве объектов.

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