Low expression of miR-182 caused by DNA hypermethylation accelerates acute lymphocyte leukemia development by targeting PBX3 and BCL2 : miR-182 promoter methylation is a predictive marker for hypomethylation agents + BCL2 inhibitor venetoclax
© 2024. The Author(s)..
BACKGROUND: miR-182 promoter hypermethylation frequently occurs in various tumors, including acute myeloid leukemia, and leads to low expression of miR-182. However, whether adult acute lymphocyte leukemia (ALL) cells have high miR-182 promoter methylation has not been determined.
METHODS: To assess the methylation status of the miR-182 promoter, methylation and unmethylation-specific PCR analysis, bisulfite-sequencing analysis, and MethylTarget™ assays were performed to measure the frequency of methylation at the miR-182 promoter. Bone marrow cells were isolated from miR-182 knockout (182KO) and 182 wild type (182WT) mice to construct BCR-ABL (P190) and Notch-induced murine B-ALL and T-ALL models, respectively. Primary ALL samples were performed to investigate synergistic effects of the hypomethylation agents (HMAs) and the BCL2 inhibitor venetoclax (Ven) in vitro.
RESULTS: miR-182 (miR-182-5P) expression was substantially lower in ALL blasts than in normal controls (NCs) because of DNA hypermethylation at the miR-182 promoter in ALL blasts but not in normal controls (NCs). Knockout of miR-182 (182KO) markedly accelerated ALL development, facilitated the infiltration, and shortened the OS in a BCR-ABL (P190)-induced murine B-ALL model. Furthermore, the 182KO ALL cell population was enriched with more leukemia-initiating cells (CD43+B220+ cells, LICs) and presented higher leukemogenic activity than the 182WT ALL population. Furthermore, depletion of miR-182 reduced the OS in a Notch-induced murine T-ALL model, suggesting that miR-182 knockout accelerates ALL development. Mechanistically, overexpression of miR-182 inhibited proliferation and induced apoptosis by directly targeting PBX3 and BCL2, two well-known oncogenes, that are key targets of miR-182. Most importantly, DAC in combination with Ven had synergistic effects on ALL cells with miR-182 promoter hypermethylation, but not on ALL cells with miR-182 promoter hypomethylation.
CONCLUSIONS: Collectively, we identified miR-182 as a tumor suppressor gene in ALL cells and low expression of miR-182 because of hypermethylation facilitates the malignant phenotype of ALL cells. DAC + Ven cotreatment might has been applied in the clinical try for ALL patients with miR-182 promoter hypermethylation. Furthermore, the methylation frequency at the miR-182 promoter should be a potential biomarker for DAC + Ven treatment in ALL patients.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
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| Enthalten in: |
Clinical epigenetics - 16(2024), 1 vom: 26. März, Seite 48 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Li, Danyang [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 27.03.2024 Date Revised 05.04.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1186/s13148-024-01658-2 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM37018193X |
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| 041 | |a eng | ||
| 100 | 1 | |a Li, Danyang |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Low expression of miR-182 caused by DNA hypermethylation accelerates acute lymphocyte leukemia development by targeting PBX3 and BCL2 |b miR-182 promoter methylation is a predictive marker for hypomethylation agents + BCL2 inhibitor venetoclax |
| 264 | 1 | |c 2024 | |
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| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 27.03.2024 | ||
| 500 | |a Date Revised 05.04.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 520 | |a BACKGROUND: miR-182 promoter hypermethylation frequently occurs in various tumors, including acute myeloid leukemia, and leads to low expression of miR-182. However, whether adult acute lymphocyte leukemia (ALL) cells have high miR-182 promoter methylation has not been determined | ||
| 520 | |a METHODS: To assess the methylation status of the miR-182 promoter, methylation and unmethylation-specific PCR analysis, bisulfite-sequencing analysis, and MethylTarget™ assays were performed to measure the frequency of methylation at the miR-182 promoter. Bone marrow cells were isolated from miR-182 knockout (182KO) and 182 wild type (182WT) mice to construct BCR-ABL (P190) and Notch-induced murine B-ALL and T-ALL models, respectively. Primary ALL samples were performed to investigate synergistic effects of the hypomethylation agents (HMAs) and the BCL2 inhibitor venetoclax (Ven) in vitro | ||
| 520 | |a RESULTS: miR-182 (miR-182-5P) expression was substantially lower in ALL blasts than in normal controls (NCs) because of DNA hypermethylation at the miR-182 promoter in ALL blasts but not in normal controls (NCs). Knockout of miR-182 (182KO) markedly accelerated ALL development, facilitated the infiltration, and shortened the OS in a BCR-ABL (P190)-induced murine B-ALL model. Furthermore, the 182KO ALL cell population was enriched with more leukemia-initiating cells (CD43+B220+ cells, LICs) and presented higher leukemogenic activity than the 182WT ALL population. Furthermore, depletion of miR-182 reduced the OS in a Notch-induced murine T-ALL model, suggesting that miR-182 knockout accelerates ALL development. Mechanistically, overexpression of miR-182 inhibited proliferation and induced apoptosis by directly targeting PBX3 and BCL2, two well-known oncogenes, that are key targets of miR-182. Most importantly, DAC in combination with Ven had synergistic effects on ALL cells with miR-182 promoter hypermethylation, but not on ALL cells with miR-182 promoter hypomethylation | ||
| 520 | |a CONCLUSIONS: Collectively, we identified miR-182 as a tumor suppressor gene in ALL cells and low expression of miR-182 because of hypermethylation facilitates the malignant phenotype of ALL cells. DAC + Ven cotreatment might has been applied in the clinical try for ALL patients with miR-182 promoter hypermethylation. Furthermore, the methylation frequency at the miR-182 promoter should be a potential biomarker for DAC + Ven treatment in ALL patients | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Acute lymphoblastic leukemia | |
| 650 | 4 | |a BCL2 | |
| 650 | 4 | |a DNA hypermethylation | |
| 650 | 4 | |a Hypomethylation agents | |
| 650 | 4 | |a microRNA | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a BCL2 protein, human |2 NLM | |
| 650 | 7 | |a Bridged Bicyclo Compounds, Heterocyclic |2 NLM | |
| 650 | 7 | |a MicroRNAs |2 NLM | |
| 650 | 7 | |a Mirn182 microRNA, human |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins c-bcl-2 |2 NLM | |
| 650 | 7 | |a Sulfonamides |2 NLM | |
| 650 | 7 | |a venetoclax |2 NLM | |
| 650 | 7 | |a N54AIC43PW |2 NLM | |
| 650 | 7 | |a proto-oncogene protein Pbx3 |2 NLM | |
| 650 | 7 | |a 146150-81-4 |2 NLM | |
| 650 | 7 | |a Homeodomain Proteins |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins |2 NLM | |
| 700 | 1 | |a Yuan, Yigang |e verfasserin |4 aut | |
| 700 | 1 | |a Meng, Chen |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Zihan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Shi, Liuzhi |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Min |e verfasserin |4 aut | |
| 700 | 1 | |a Ye, Daijiao |e verfasserin |4 aut | |
| 700 | 1 | |a Cai, Yue |e verfasserin |4 aut | |
| 700 | 1 | |a He, Xiaofei |e verfasserin |4 aut | |
| 700 | 1 | |a Ye, Haige |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Shujuan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Haixia |e verfasserin |4 aut | |
| 700 | 1 | |a Gao, Shenmeng |e verfasserin |4 aut | |
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