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

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.