Cancer medicine · 2025
Inhibiting H3K27 Demethylases Downregulates CREB-CREBBP, Overcoming Resistance in Relapsed Acute Lymphoblastic Leukemia.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Lazaro-Navarro Juan, Alcon Clara, Dorel Mathurin, Alasfar Lina, Bastian Lorenz, Baldus Claudia, Astrahantseff Kathy, Yaspo Marie-Laure, Montero Joan, Eckert Cornelia
Аннотация
BACKGROUND: CREB binding protein (CREBBP) is a key epigenetic regulator, altered in a fifth of relapsed cases of acute lymphoblastic leukemia (ALL). Selectively targeting epigenetic signaling may be an effective novel therapeutic approach to overcome drug resistance. Anti-tumor effects have previously been demonstrated for GSK-J4, a selective H3K27 histone demethylase inhibitor, in several animal models of cancers.
METHODS: To characterize the effect of GSK-J4, drug response profiling, CRISPR-Dropout Screening, BH3 profiling and immunoblotting were carried out in ALL cell lines or patient derived samples.
RESULTS: Here we provide evidence that GSK-J4 downregulates cyclic AMP-responsive element-binding protein (CREB) and CREBBP in B-cell precursor-ALL cell lines and patient samples. High CREBBP expression in BCP-ALL cell lines correlated with high GSK-J4 sensitivity and low dexamethasone sensitivity. GSK-J4 treatment also induced Bcl-2 and Bcl-XL dependency and apoptosis.
CONCLUSIONS: This study proposes H3K27 demethylase inhibition as a potential treatment strategy for patients with treatment-resistant ALL, using CREBBP as a biomarker for drug response and combining GSK-J4 with venetoclax and navitoclax as synergistic partners.
METHODS: To characterize the effect of GSK-J4, drug response profiling, CRISPR-Dropout Screening, BH3 profiling and immunoblotting were carried out in ALL cell lines or patient derived samples.
RESULTS: Here we provide evidence that GSK-J4 downregulates cyclic AMP-responsive element-binding protein (CREB) and CREBBP in B-cell precursor-ALL cell lines and patient samples. High CREBBP expression in BCP-ALL cell lines correlated with high GSK-J4 sensitivity and low dexamethasone sensitivity. GSK-J4 treatment also induced Bcl-2 and Bcl-XL dependency and apoptosis.
CONCLUSIONS: This study proposes H3K27 demethylase inhibition as a potential treatment strategy for patients with treatment-resistant ALL, using CREBBP as a biomarker for drug response and combining GSK-J4 with venetoclax and navitoclax as synergistic partners.