MLN4924 Suppresses Acute Myeloid Leukemia Progression by LINC01128-Driven Epigenetic Reactivation of TRIM58

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 ChinaCorrespondence: Bei Liu, Department of Hematology, The First Hospital of Lanzhou University, Lanzhou, People’s Republic of China, Email [email protected]: 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