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
Abstract 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...
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| Format: | Article |
| Language: | English |
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BMC
2024-03-01
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| Series: | Clinical Epigenetics |
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| Online Access: | https://doi.org/10.1186/s13148-024-01658-2 |
| _version_ | 1797233486270038016 |
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| author | Danyang Li Yigang Yuan Chen Meng Zihan Lin Min Zhao Liuzhi Shi Min Li Daijiao Ye Yue Cai Xiaofei He Haige Ye Shujuan Zhou Haixia Zhou Shenmeng Gao |
| author_facet | Danyang Li Yigang Yuan Chen Meng Zihan Lin Min Zhao Liuzhi Shi Min Li Daijiao Ye Yue Cai Xiaofei He Haige Ye Shujuan Zhou Haixia Zhou Shenmeng Gao |
| author_sort | Danyang Li |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-24T16:16:56Z |
| format | Article |
| id | doaj.art-c44c05750ee741bc967316cdfdac82e9 |
| institution | Directory Open Access Journal |
| issn | 1868-7083 |
| language | English |
| last_indexed | 2024-04-24T16:16:56Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Clinical Epigenetics |
| spelling | doaj.art-c44c05750ee741bc967316cdfdac82e92024-03-31T11:23:57ZengBMCClinical Epigenetics1868-70832024-03-0116111710.1186/s13148-024-01658-2Low 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 venetoclaxDanyang Li0Yigang Yuan1Chen Meng2Zihan Lin3Min Zhao4Liuzhi Shi5Min Li6Daijiao Ye7Yue Cai8Xiaofei He9Haige Ye10Shujuan Zhou11Haixia Zhou12Shenmeng Gao13Medical Research Center, The First Affiliated Hospital of Wenzhou Medical UniversityMedical Research Center, The First Affiliated Hospital of Wenzhou Medical UniversityMedical Research Center, The First Affiliated Hospital of Wenzhou Medical UniversityMedical Research Center, The First Affiliated Hospital of Wenzhou Medical UniversityMedical Research Center, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical UniversityMedical Research Center, The First Affiliated Hospital of Wenzhou Medical UniversityMedical Research Center, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Clinical Medicine, Wenzhou Medical UniversityMedical Research Center, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Hematology, The First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Hematology, The First Affiliated Hospital of Wenzhou Medical UniversityThe Key Laboratory of Pediatric Hematology and Oncology Diseases of Wenzhou, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical UniversityMedical Research Center, The First Affiliated Hospital of Wenzhou Medical UniversityAbstract 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.https://doi.org/10.1186/s13148-024-01658-2DNA hypermethylationHypomethylation agentsAcute lymphoblastic leukemiamicroRNABCL2 |
| spellingShingle | Danyang Li Yigang Yuan Chen Meng Zihan Lin Min Zhao Liuzhi Shi Min Li Daijiao Ye Yue Cai Xiaofei He Haige Ye Shujuan Zhou Haixia Zhou Shenmeng Gao 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 Clinical Epigenetics DNA hypermethylation Hypomethylation agents Acute lymphoblastic leukemia microRNA BCL2 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | DNA hypermethylation Hypomethylation agents Acute lymphoblastic leukemia microRNA BCL2 |
| url | https://doi.org/10.1186/s13148-024-01658-2 |
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