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Hypoxia impairs decitabine-induced expression of HLA-DR in acute myeloid leukaemia cell lines [RNA-seq]

ABSTRACT: Background Hypomethylating agents (HMA), such as azacytidine (AZA) and decitabine (DAC), are epigenetic therapies used to treat some patients with acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). HMAs act in a replication-dependent manner to remove DNA methylation from the genome. However, AML cells targeted by HMA therapy are often quiescent within the bone marrow, where oxygen levels are low. In this study, we investigate the effects of hypoxia on HMA responses in AML cells. Results AML cell lines (MOLM-13, MV-4-11, HL-60) were treated with DAC (100nM) or AZA (500-2000nM) in normoxic (21% O2) and hypoxic (1% O2) conditions. Hypoxia significantly reduced AML cell growth and colony-forming capacity across all cell lines, with no additional effects observed upon HMA treatment. Hypoxia had no impact on the extent of DNA hypomethylation induced by DAC treatment, but limited AZA-induced loss of methylation from the genome. Transcriptional responses to HMA treatment were also altered, with HMAs failing to up-regulate antigen presentation pathways in hypoxia. In particular, cell surface expression of the MHC class II receptor, HLA-DR, was increased by DAC treatment in normoxia, but not hypoxia. Conclusion Our results suggest that HMA-induced antigen presentation may be impaired by hypoxia. This study highlights the need to consider microenvironmental factors when designing co-treatment strategies to improve HMA therapeutic efficacy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285257 | GEO | 2025/01/29

REPOSITORIES: GEO

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Hypoxia impairs decitabine-induced expression of HLA-DR in acute myeloid leukaemia cell lines [Bisulfite-Seq]

Project description:Background Hypomethylating agents (HMA), such as azacytidine (AZA) and decitabine (DAC), are epigenetic therapies used to treat some patients with acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). HMAs act in a replication-dependent manner to remove DNA methylation from the genome. However, AML cells targeted by HMA therapy are often quiescent within the bone marrow, where oxygen levels are low. In this study, we investigate the effects of hypoxia on HMA responses in AML cells. Results AML cell lines (MOLM-13, MV-4-11, HL-60) were treated with DAC (100nM) or AZA (500-2000nM) in normoxic (21% O2) and hypoxic (1% O2) conditions. Hypoxia significantly reduced AML cell growth and colony-forming capacity across all cell lines, with no additional effects observed upon HMA treatment. Hypoxia had no impact on the extent of DNA hypomethylation induced by DAC treatment, but limited AZA-induced loss of methylation from the genome. Transcriptional responses to HMA treatment were also altered, with HMAs failing to up-regulate antigen presentation pathways in hypoxia. In particular, cell surface expression of the MHC class II receptor, HLA-DR, was increased by DAC treatment in normoxia, but not hypoxia. Conclusion Our results suggest that HMA-induced antigen presentation may be impaired by hypoxia. This study highlights the need to consider microenvironmental factors when designing co-treatment strategies to improve HMA therapeutic efficacy.

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2024-07-24 | GSE261338 | GEO

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Gene expression data of serially sorted primary AML patient blasts prior and after treatment with the DNMT inhibitor decitabine (DAC)

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2024-04-17 | PXD038663 | Pride

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Project description:Azacitidine (AZA) is a DNA methyltransferase inhibitor and epigenetic modulator that can be an effective agent in combination with chemotherapy for patients with high-risk acute myeloid leukemia (AML). However, biological factors driving the therapeutic response of such hypomethylating agent (HMA)-based therapies remain unknown. Herein, the transcriptome and/or genome-wide 5-hydroxymethylcytosine (5hmC) are characterized for 41 patients with high-risk AML from a phase 1 clinical trial treated with AZA epigenetic priming followed by high-dose cytarabine and mitoxantrone (AZA-HiDAC-Mito). Digital cytometry reveals that responders have elevated Granulocyte-macrophage-progenitor-like (GMP-like) malignant cells displaying an active cell cycle program. Moreover, the enrichment of Natural killer (NK) cells predicts favorable outcome in patients receiving AZA-HiDAC-Mito therapy or other AZA-based therapies. Comparing 5hmC profiles before and after five-day treatment of AZA shows that AZA exposure induces dose-dependent 5hmC changes, the magnitude of which predicts overall survival (p=0.015). An XGBoost machine learning model is developed to predict the treatment response based on 5hmC levels of only 11 genes, achieving an area under the curve (AUC) of 0.860. These results suggest that cellular composition markedly impacts the treatment response, and showcase the prospect of 5hmC signature in predicting the outcomes of HMA-based therapies in AML.

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Project description:Epigenetic therapy, using hypomethylating agents (HMA), is known to be effective in the treatment of high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients who are not suitable for intensive chemotherapy or allogeneic stem cell transplantation. However, response rates to HMA are low and there is an unmet need in finding prognostic and predictive biomarkers of treatment response. We performed global methylation analysis of 75 patients with high risk MDS and secondary AML (sAML) who were included in CETLAM MDS-09 protocol, in which patients received HMA or intensive treatment according to age, comorbidities and cytogenetics. At diagnosis, no global methylation pattern allowed us to differentiate patients according to the cytological subtype, cytogenetics or treatment response. But we found a methylation signature defined by 200 probes, which allowed us to distinguish between responding and non-responding patients to azacitidine (AZA) treatment. Studying follow-up samples, we have confirmed that AZA decreases global DNA methylation, but in our cohort the degree of methylation decrease did not correlate with the type of response. The methylation signature detected at diagnosis was not useful in treated samples to determine a methylation pattern predictive of progression or relapse. In conclusion, altered DNA methylation patterns at diagnosis, in a subset of determined CpGs, may serve as biomarker for predicting AZA response.

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