Hypoxia impairs decitabine-induced expression of HLA-DR in acute myeloid leukaemia cell lines
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. HMAs act in a replication-dependent manner to remove DNA methylation from the genome...
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BMC
2025-01-01
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| Series: | Clinical Epigenetics |
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| Online Access: | https://doi.org/10.1186/s13148-025-01812-4 |
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| author | Sam Humphries Sean M. Burnard Courtney D. Eggins Simon Keely Danielle R. Bond Heather J. Lee |
| author_facet | Sam Humphries Sean M. Burnard Courtney D. Eggins Simon Keely Danielle R. Bond Heather J. Lee |
| author_sort | Sam Humphries |
| collection | DOAJ |
| description | 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. 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 (100 nM) or AZA (500–2000 nM) in normoxic (21% O2) and hypoxic (1% O2) conditions. Hypoxia significantly reduced AML cell growth 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. |
| format | Article |
| id | doaj-art-d18e7a95e1dc4d92af998d596d011e66 |
| institution | Kabale University |
| issn | 1868-7083 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Clinical Epigenetics |
| spelling | doaj-art-d18e7a95e1dc4d92af998d596d011e662025-01-19T12:27:50ZengBMCClinical Epigenetics1868-70832025-01-0117111210.1186/s13148-025-01812-4Hypoxia impairs decitabine-induced expression of HLA-DR in acute myeloid leukaemia cell linesSam Humphries0Sean M. Burnard1Courtney D. Eggins2Simon Keely3Danielle R. Bond4Heather J. Lee5School of Biomedical Sciences and Pharmacy, The University of NewcastleSchool of Biomedical Sciences and Pharmacy, The University of NewcastleSchool of Biomedical Sciences and Pharmacy, The University of NewcastleSchool of Biomedical Sciences and Pharmacy, The University of NewcastleSchool of Biomedical Sciences and Pharmacy, The University of NewcastleSchool of Biomedical Sciences and Pharmacy, The University of NewcastleAbstract 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. 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 (100 nM) or AZA (500–2000 nM) in normoxic (21% O2) and hypoxic (1% O2) conditions. Hypoxia significantly reduced AML cell growth 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.https://doi.org/10.1186/s13148-025-01812-4Acute myeloid leukaemiaHypoxiaHypomethylating agentsHuman leukocyte antigens |
| spellingShingle | Sam Humphries Sean M. Burnard Courtney D. Eggins Simon Keely Danielle R. Bond Heather J. Lee Hypoxia impairs decitabine-induced expression of HLA-DR in acute myeloid leukaemia cell lines Clinical Epigenetics Acute myeloid leukaemia Hypoxia Hypomethylating agents Human leukocyte antigens |
| title | Hypoxia impairs decitabine-induced expression of HLA-DR in acute myeloid leukaemia cell lines |
| title_full | Hypoxia impairs decitabine-induced expression of HLA-DR in acute myeloid leukaemia cell lines |
| title_fullStr | Hypoxia impairs decitabine-induced expression of HLA-DR in acute myeloid leukaemia cell lines |
| title_full_unstemmed | Hypoxia impairs decitabine-induced expression of HLA-DR in acute myeloid leukaemia cell lines |
| title_short | Hypoxia impairs decitabine-induced expression of HLA-DR in acute myeloid leukaemia cell lines |
| title_sort | hypoxia impairs decitabine induced expression of hla dr in acute myeloid leukaemia cell lines |
| topic | Acute myeloid leukaemia Hypoxia Hypomethylating agents Human leukocyte antigens |
| url | https://doi.org/10.1186/s13148-025-01812-4 |
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