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2025-01-10

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cc-by (c) Juan Lazaro-Navarro et al., 2025
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/219304

Inhibiting H3K27 Demethylases Downregulates CREB-CREBBP, Overcoming Resistance in Relapsed Acute Lymphoblastic Leukemia

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https://doi.org/https://doi.org/10.1002/cam4.70596

Resum

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.

Matèries

Epigenètica, Leucèmia, Apoptosi

Matèries (anglès)

Epigenetics, Leukemia, Apoptosis

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Articles publicats en revistes (Biomedicina)

Citació

LAZARO NAVARRO, Juan, et al. Inhibiting H3K27 Demethylases Downregulates CREB-CREBBP, Overcoming Resistance in Relapsed Acute Lymphoblastic Leukemia. Cancer Medicine. 2025. Vol. 14, num. 1, pags. 1-7. ISSN 2045-7634. [consulted: 19 of August of 2026]. Available at: https://hdl.handle.net/2445/219304

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