Inhibiting H3K27 Demethylases Downregulates CREB‐CREBBP, Overcoming Resistance in Relapsed Acute Lymphoblastic Leukemia
ABSTRACT 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...
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2025-01-01
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| Online Access: | https://doi.org/10.1002/cam4.70596 |
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| author | Juan Lazaro‐Navarro Clara Alcon Mathurin Dorel Lina Alasfar Lorenz Bastian Claudia Baldus Kathy Astrahantseff Marie‐Laure Yaspo Joan Montero Cornelia Eckert |
| author_facet | Juan Lazaro‐Navarro Clara Alcon Mathurin Dorel Lina Alasfar Lorenz Bastian Claudia Baldus Kathy Astrahantseff Marie‐Laure Yaspo Joan Montero Cornelia Eckert |
| author_sort | Juan Lazaro‐Navarro |
| collection | DOAJ |
| description | ABSTRACT 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. |
| format | Article |
| id | doaj-art-4f41db4e65a74ff4b1eac8b7e7ebef07 |
| institution | Kabale University |
| issn | 2045-7634 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Cancer Medicine |
| spelling | doaj-art-4f41db4e65a74ff4b1eac8b7e7ebef072025-01-13T13:22:39ZengWileyCancer Medicine2045-76342025-01-011411710.1002/cam4.70596Inhibiting H3K27 Demethylases Downregulates CREB‐CREBBP, Overcoming Resistance in Relapsed Acute Lymphoblastic LeukemiaJuan Lazaro‐Navarro0Clara Alcon1Mathurin Dorel2Lina Alasfar3Lorenz Bastian4Claudia Baldus5Kathy Astrahantseff6Marie‐Laure Yaspo7Joan Montero8Cornelia Eckert9Department of Pediatric Oncology/Hematology Charité‐Universitätsmedizin Berlin Berlin GermanyDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences University of Barcelona Barcelona SpainMax Planck Institute for Molecular Genetics Berlin GermanyDepartment of Pediatric Oncology/Hematology Charité‐Universitätsmedizin Berlin Berlin GermanyMedical Department II, Hematology/Oncology University Medical Center Schleswig‐Holstein Campus Kiel GermanyMedical Department II, Hematology/Oncology University Medical Center Schleswig‐Holstein Campus Kiel GermanyDepartment of Pediatric Oncology/Hematology Charité‐Universitätsmedizin Berlin Berlin GermanyMax Planck Institute for Molecular Genetics Berlin GermanyDepartment of Biomedical Sciences, Faculty of Medicine and Health Sciences University of Barcelona Barcelona SpainDepartment of Pediatric Oncology/Hematology Charité‐Universitätsmedizin Berlin Berlin GermanyABSTRACT 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.https://doi.org/10.1002/cam4.70596apoptosisdrug discovery and deliveryepigeneticsleukemia |
| spellingShingle | Juan Lazaro‐Navarro Clara Alcon Mathurin Dorel Lina Alasfar Lorenz Bastian Claudia Baldus Kathy Astrahantseff Marie‐Laure Yaspo Joan Montero Cornelia Eckert Inhibiting H3K27 Demethylases Downregulates CREB‐CREBBP, Overcoming Resistance in Relapsed Acute Lymphoblastic Leukemia Cancer Medicine apoptosis drug discovery and delivery epigenetics leukemia |
| title | Inhibiting H3K27 Demethylases Downregulates CREB‐CREBBP, Overcoming Resistance in Relapsed Acute Lymphoblastic Leukemia |
| title_full | Inhibiting H3K27 Demethylases Downregulates CREB‐CREBBP, Overcoming Resistance in Relapsed Acute Lymphoblastic Leukemia |
| title_fullStr | Inhibiting H3K27 Demethylases Downregulates CREB‐CREBBP, Overcoming Resistance in Relapsed Acute Lymphoblastic Leukemia |
| title_full_unstemmed | Inhibiting H3K27 Demethylases Downregulates CREB‐CREBBP, Overcoming Resistance in Relapsed Acute Lymphoblastic Leukemia |
| title_short | Inhibiting H3K27 Demethylases Downregulates CREB‐CREBBP, Overcoming Resistance in Relapsed Acute Lymphoblastic Leukemia |
| title_sort | inhibiting h3k27 demethylases downregulates creb crebbp overcoming resistance in relapsed acute lymphoblastic leukemia |
| topic | apoptosis drug discovery and delivery epigenetics leukemia |
| url | https://doi.org/10.1002/cam4.70596 |
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