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

• Published in: Clinical epigenetics Vol. 16; no. 1; p. 48
• Main Authors: Li, Danyang, Yuan, Yigang, Meng, Chen, Lin, Zihan, Zhao, Min, Shi, Liuzhi, Li, Min, Ye, Daijiao, Cai, Yue, He, Xiaofei, Ye, Haige, Zhou, Shujuan, Zhou, Haixia, Gao, Shenmeng
• Format: Journal Article
• Language: English
• Published: Germany BioMed Central Ltd 26.03.2024; BioMed Central; BMC
• Subjects: Abl protein; Acute lymphoblastic leukemia; Acute myeloid leukemia; Adult; Animal models; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Bcl-2 protein; BCL2; BCR protein; Bisulfite; Bone marrow; Bridged Bicyclo Compounds, Heterocyclic; Cancer; CD43 antigen; Chemotherapy; Clinical outcomes; Cytokines; DNA; DNA - metabolism; DNA hypermethylation; DNA Methylation; Ethics; Fusion protein; Genes; Genetic aspects; Humans; Hypomethylation agents; Leukemia; Lymphocytes; Lymphocytes - metabolism; Lymphocytes T; Metastases; Methylation; Mice; Mice, Knockout; MicroRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - metabolism; Patients; Phenotypes; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Sequence analysis; Stem cells; Sulfites; Sulfonamides; Tumor suppressor genes; China; Beijing China; United States > US; BCL2; DNA hypermethylation; microRNA; Acute lymphoblastic leukemia; Hypomethylation agents
• ISSN: 1868-7083; 1868-7075; 1868-7083; 1868-7075
• DOI: 10.1186/s13148-024-01658-2

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. 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. 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. 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.