Deubiquitinating enzyme inhibitor alleviates cyclin A1‐mediated proteasome inhibitor tolerance in mixed‐lineage leukemia

Drug resistance is a significant obstacle to effective cancer treatment. Drug resistance develops from initially reversible drug‐tolerant cancer cells, which offer 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 remain largely unknown. 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 downregulation 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. 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. Cyclin A1 suppression elicits the development of transient proteasome inhibitor (PI) tolerance in mixed‐lineage leukemia cells. Reduction of MLL and cyclin A1 is associated with patient relapse and reduced survival in acute lymphoblastic leukemia. Combined PI with deubiquitinating enzyme (DUB) inhibitors overcomes drug resistance by restoring cyclin A1 expression through chromatin crosstalk. Cell‐cycle re‐entry by DUB inhibitors represents a potential therapeutic strategy to prevent acquired drug resistance.