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.