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已发表论文
MLN4924 通过 LINC01128 驱动的 TRIM58 表观遗传再激活抑制急性髓系白血病进展
Authors Guo Y , Jian J , Tang X , An S, Zhao L, Chen R , Ma W , Liu B
Received 20 May 2025
Accepted for publication 1 October 2025
Published 22 October 2025 Volume 2025:19 Pages 9439—9456
DOI https://doi.org/10.2147/DDDT.S541720
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Anastasios Lymperopoulos
Yuancheng Guo,1– 3 Jinli Jian,3 Xiao Tang,3 Shujuan An,3,4 Long Zhao,1,3 Run Chen,3 Weiqing Ma,5 Bei Liu1– 3
1Department of Hematology, The First Hospital of Lanzhou University, Lanzhou, 730000, People’s Republic of China; 2Gansu Provincial Clinical Medical Research Center for Molecular Diagnosis and Treatment of Hematological Diseases, Lanzhou, 730000, People’s Republic of China; 3The First Clinical Medical School, Lanzhou University, Lanzhou, 730000, People’s Republic of China; 4Department of Medical Laboratory, The First Hospital of Lanzhou University, Lanzhou, 730000, People’s Republic of China; 5School of Public Health, Lanzhou University, Lanzhou, 730000, People’s Republic of China
Correspondence: Bei Liu, Department of Hematology, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China, Email liubei@lzu.edu.cn
Purpose: The aim of this study was to elucidate the molecular mechanism by which MLN4924 affects the progression of acute myeloid leukemia (AML) by regulating TRIM58 DNA methylation.
Patients and Methods: Gene expression was analyzed by RT-qPCR and Western blot, while methylation changes were assessed via Methylation-sensitive restriction enzyme-quantitative PCR. Differentially expressed lncRNAs were identified through RNA sequencing. Subcellular localization was determined via nuclear-cytoplasmic fractionation-PCR. Protein-DNA/RNA interactions were analyzed by chromatin immunoprecipitation and RNA immunoprecipitation, respectively. In vivo experiments were conducted using a xenograft model, with tumor protein expression evaluated by immunohistochemistry.
Results: TRIM58 downregulation in AML correlated with promoter hypermethylation, reversible by MLN4924 treatment. Functional studies demonstrated TRIM58 mediated MLN4924-induced apoptosis through AKT pathway inhibition. While MLN4924 upregulated the tumor-suppressive lncRNA LINC01128, its overexpression recapitulated TRIM58-mediated anti-leukemic effects, including expansion arrest, apoptosis induction, and BAX/BCL-2 axis modulation. Mechanistically, nuclear-localized LINC011128 functionally interacted with DNMT1 to mediate TRIM58 promoter demethylation, establishing an epigenetic regulatory axis. Rescue experiments revealed TRIM58 knockdown attenuated MLN4924’s suppression of AKT phosphorylation and associated pro-apoptotic effects.
Conclusion: In this study, we show that MLN4924 can upregulate LINC01128, which binds to and segregates DNMT1, thereby inhibiting methylation modification of the TRIM58 and ultimately suppressing AML.
Keywords: DNA methylation, DNMT1, lncRNA LINC01128, proximal promoter
1Department of Hematology, The First Hospital of Lanzhou University, Lanzhou, 730000, People’s Republic of China; 2Gansu Provincial Clinical Medical Research Center for Molecular Diagnosis and Treatment of Hematological Diseases, Lanzhou, 730000, People’s Republic of China; 3The First Clinical Medical School, Lanzhou University, Lanzhou, 730000, People’s Republic of China; 4Department of Medical Laboratory, The First Hospital of Lanzhou University, Lanzhou, 730000, People’s Republic of China; 5School of Public Health, Lanzhou University, Lanzhou, 730000, People’s Republic of China
Correspondence: Bei Liu, Department of Hematology, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China, Email liubei@lzu.edu.cn
Purpose: The aim of this study was to elucidate the molecular mechanism by which MLN4924 affects the progression of acute myeloid leukemia (AML) by regulating TRIM58 DNA methylation.
Patients and Methods: Gene expression was analyzed by RT-qPCR and Western blot, while methylation changes were assessed via Methylation-sensitive restriction enzyme-quantitative PCR. Differentially expressed lncRNAs were identified through RNA sequencing. Subcellular localization was determined via nuclear-cytoplasmic fractionation-PCR. Protein-DNA/RNA interactions were analyzed by chromatin immunoprecipitation and RNA immunoprecipitation, respectively. In vivo experiments were conducted using a xenograft model, with tumor protein expression evaluated by immunohistochemistry.
Results: TRIM58 downregulation in AML correlated with promoter hypermethylation, reversible by MLN4924 treatment. Functional studies demonstrated TRIM58 mediated MLN4924-induced apoptosis through AKT pathway inhibition. While MLN4924 upregulated the tumor-suppressive lncRNA LINC01128, its overexpression recapitulated TRIM58-mediated anti-leukemic effects, including expansion arrest, apoptosis induction, and BAX/BCL-2 axis modulation. Mechanistically, nuclear-localized LINC011128 functionally interacted with DNMT1 to mediate TRIM58 promoter demethylation, establishing an epigenetic regulatory axis. Rescue experiments revealed TRIM58 knockdown attenuated MLN4924’s suppression of AKT phosphorylation and associated pro-apoptotic effects.
Conclusion: In this study, we show that MLN4924 can upregulate LINC01128, which binds to and segregates DNMT1, thereby inhibiting methylation modification of the TRIM58 and ultimately suppressing AML.
Keywords: DNA methylation, DNMT1, lncRNA LINC01128, proximal promoter