Deubiquitinating Enzyme Inhibitor Alleviates Cyclin A1-mediated Proteasome Inhibitor Tolerance in Mixed-lineage Leukemia

Abstract

Background: Drug resistance is a significant obstacle to effective cancer treatment. Drug resistance develops from initially reversible drug-tolerant cancer cells, which offers therapeutic opportunities to impede cancer relapse. The mechanisms of resistance to proteasome inhibitor (PI) therapy have been investigated intensively; however, the ways by which drug-tolerant cancer cells orchestrate their adaptive responses to drug challenges remains largely unknown. Methods: RNA sequencing and bioinformatics analyses were employed to assess dysregulated cell cycle genes. Chromatin immunoprecipitation assays were performed to evaluate the involvement of MLL in cyclin A1 transcriptional activity. Cell cycle assays, cell viability assays, immunoblots, and apoptosis assays were performed to evaluate the dependency of cyclin A1 during tolerance acquisition.Results: Here, we demonstrated that cyclin A1 suppression elicited the development of transient PI tolerance in mixed-lineage leukemia (MLL) cells. This adaptive process involved reversible down-regulation of cyclin A1, which promoted PI resistance through cell cycle arrest. PI-tolerant MLL cells acquired cyclin A1 dependency, regulated directly by MLL protein. Loss of cyclin A1 function resulted in the emergence of drug tolerance, which was associated with patient relapse and reduced survival. Combination treatment with PI and deubiquitinating enzyme (DUB) inhibitors overcame this drug resistance by restoring cyclin A1 expression through chromatin crosstalk between histone H2B monoubiquitination and MLL-mediated histone H3 lysine 4 methylation. Conclusion: These results reveal the importance of cyclin A1-engaged cell cycle regulation in PI resistance in MLL cells, and suggest that cell cycle re-entry by DUB inhibitors may represent a promising epigenetic therapeutic strategy to prevent acquired drug resistance.

Erratum

“…In an article 1 titled “Deubiquitinating enzyme inhibitor alleviates cyclin A1‐mediated proteasome inhibitor tolerance in mixed‐lineage leukemia” by Maolin Ge, Qiongyu Xu, Ting Kang, Dan Li, Ruiheng Wang, Zhihong Chen, Shufeng Xie, Wenbin Wang, and Han Liu, the below footnote should have appeared on the first page.…”