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

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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.

# metadata.dc.rights[].value
cc-by (c)  Juan Lazaro-Navarro et al., 2025

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Articles publicats en revistes (Biomedicina)

# metadata.dc.title[].value
Inhibiting H3K27 Demethylases Downregulates CREB-CREBBP, Overcoming Resistance in Relapsed Acute Lymphoblastic Leukemia