Epigenetic Silencing of <i>PTEN</i> and Epi-Transcriptional Silencing of <i>MDM2</i> Underlied Progression to Secondary Acute Myeloid Leukemia in Myelodysplastic Syndrome Treated with Hypomethylating Agents
In myelodysplastic syndrome (MDS), resistance to hypomethylating agents (HMA) portends a poor prognosis, underscoring the importance of understanding the molecular mechanisms leading to HMA-resistance. In this study, P39 and Kasumi-1 cells and their azacitidine-resistant and decitabine-resistant sub...
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MDPI AG
2022-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/10/5670 |
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| author | Paul Lee Rita Yim Kai-Kei Miu Sin-Hang Fung Jason Jinyue Liao Zhangting Wang Jun Li Yammy Yung Hiu-Tung Chu Pui-Kwan Yip Emily Lee Eric Tse Yok-Lam Kwong Harinder Gill |
| author_facet | Paul Lee Rita Yim Kai-Kei Miu Sin-Hang Fung Jason Jinyue Liao Zhangting Wang Jun Li Yammy Yung Hiu-Tung Chu Pui-Kwan Yip Emily Lee Eric Tse Yok-Lam Kwong Harinder Gill |
| author_sort | Paul Lee |
| collection | DOAJ |
| description | In myelodysplastic syndrome (MDS), resistance to hypomethylating agents (HMA) portends a poor prognosis, underscoring the importance of understanding the molecular mechanisms leading to HMA-resistance. In this study, P39 and Kasumi-1 cells and their azacitidine-resistant and decitabine-resistant sublines were evaluated comparatively with transcriptomic and methylomic analyses. Expression profiling and genome-wide methylation microarray showed downregulation of <i>PTEN</i> associated with DNA hypermethylation in P39 cell lines resistant to azacitidine and decitabine. This pattern of <i>PTEN</i> dysregulation was also confirmed in a cohort of patients failing treatment with HMA. DNA hypomethylation of <i>MDM2</i> was detected with downregulation of <i>MDM2</i> in HMA resistant cell lines. Long-read sequencing revealed significant RNA hypomethylation of <i>MDM2</i> resulting in alternative splicing and production of a truncated <i>MDM2</i> transcript in azacitidine-resistant P39 cells. The expression of this <i>MDM2</i> truncated transcript was also significantly increased in HMA-resistant patients compared with HMA-responsive patients. In conclusion, epigenetic and epi-transcriptomic dysregulation of <i>PTEN</i> and <i>MDM2</i> were associated with resistance to hypomethylating agents. |
| first_indexed | 2024-03-10T03:43:12Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T03:43:12Z |
| publishDate | 2022-05-01 |
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| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-242f13a9adea43ac815fe4e8db79d8432023-11-23T11:26:34ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-05-012310567010.3390/ijms23105670Epigenetic Silencing of <i>PTEN</i> and Epi-Transcriptional Silencing of <i>MDM2</i> Underlied Progression to Secondary Acute Myeloid Leukemia in Myelodysplastic Syndrome Treated with Hypomethylating AgentsPaul Lee0Rita Yim1Kai-Kei Miu2Sin-Hang Fung3Jason Jinyue Liao4Zhangting Wang5Jun Li6Yammy Yung7Hiu-Tung Chu8Pui-Kwan Yip9Emily Lee10Eric Tse11Yok-Lam Kwong12Harinder Gill13Department of Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaDepartment of Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaSchool of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, ChinaSchool of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, ChinaDepartment of Chemical Pathology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, ChinaSchool of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, ChinaDepartment of Infectious Diseases and Public Health, The City University of Hong Kong, Hong Kong, ChinaDepartment of Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaDepartment of Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaDepartment of Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaDepartment of Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaDepartment of Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaDepartment of Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaDepartment of Medicine, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, ChinaIn myelodysplastic syndrome (MDS), resistance to hypomethylating agents (HMA) portends a poor prognosis, underscoring the importance of understanding the molecular mechanisms leading to HMA-resistance. In this study, P39 and Kasumi-1 cells and their azacitidine-resistant and decitabine-resistant sublines were evaluated comparatively with transcriptomic and methylomic analyses. Expression profiling and genome-wide methylation microarray showed downregulation of <i>PTEN</i> associated with DNA hypermethylation in P39 cell lines resistant to azacitidine and decitabine. This pattern of <i>PTEN</i> dysregulation was also confirmed in a cohort of patients failing treatment with HMA. DNA hypomethylation of <i>MDM2</i> was detected with downregulation of <i>MDM2</i> in HMA resistant cell lines. Long-read sequencing revealed significant RNA hypomethylation of <i>MDM2</i> resulting in alternative splicing and production of a truncated <i>MDM2</i> transcript in azacitidine-resistant P39 cells. The expression of this <i>MDM2</i> truncated transcript was also significantly increased in HMA-resistant patients compared with HMA-responsive patients. In conclusion, epigenetic and epi-transcriptomic dysregulation of <i>PTEN</i> and <i>MDM2</i> were associated with resistance to hypomethylating agents.https://www.mdpi.com/1422-0067/23/10/5670PTENMDM2myelodysplastic syndromehypomethylating agentsresistance |
| spellingShingle | Paul Lee Rita Yim Kai-Kei Miu Sin-Hang Fung Jason Jinyue Liao Zhangting Wang Jun Li Yammy Yung Hiu-Tung Chu Pui-Kwan Yip Emily Lee Eric Tse Yok-Lam Kwong Harinder Gill Epigenetic Silencing of <i>PTEN</i> and Epi-Transcriptional Silencing of <i>MDM2</i> Underlied Progression to Secondary Acute Myeloid Leukemia in Myelodysplastic Syndrome Treated with Hypomethylating Agents International Journal of Molecular Sciences PTEN MDM2 myelodysplastic syndrome hypomethylating agents resistance |
| title | Epigenetic Silencing of <i>PTEN</i> and Epi-Transcriptional Silencing of <i>MDM2</i> Underlied Progression to Secondary Acute Myeloid Leukemia in Myelodysplastic Syndrome Treated with Hypomethylating Agents |
| title_full | Epigenetic Silencing of <i>PTEN</i> and Epi-Transcriptional Silencing of <i>MDM2</i> Underlied Progression to Secondary Acute Myeloid Leukemia in Myelodysplastic Syndrome Treated with Hypomethylating Agents |
| title_fullStr | Epigenetic Silencing of <i>PTEN</i> and Epi-Transcriptional Silencing of <i>MDM2</i> Underlied Progression to Secondary Acute Myeloid Leukemia in Myelodysplastic Syndrome Treated with Hypomethylating Agents |
| title_full_unstemmed | Epigenetic Silencing of <i>PTEN</i> and Epi-Transcriptional Silencing of <i>MDM2</i> Underlied Progression to Secondary Acute Myeloid Leukemia in Myelodysplastic Syndrome Treated with Hypomethylating Agents |
| title_short | Epigenetic Silencing of <i>PTEN</i> and Epi-Transcriptional Silencing of <i>MDM2</i> Underlied Progression to Secondary Acute Myeloid Leukemia in Myelodysplastic Syndrome Treated with Hypomethylating Agents |
| title_sort | epigenetic silencing of i pten i and epi transcriptional silencing of i mdm2 i underlied progression to secondary acute myeloid leukemia in myelodysplastic syndrome treated with hypomethylating agents |
| topic | PTEN MDM2 myelodysplastic syndrome hypomethylating agents resistance |
| url | https://www.mdpi.com/1422-0067/23/10/5670 |
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