In this study, we used an affinity purification and tandem mass spectrometry to identify KLHL2 and USP28 as an E3 ubiquitin ligase and deubiquitinase (DUB) respectively, which antagonistically regulate UCK1 ubiquitination in AML cells and may represent a novel mechanism for relapse or refractoriness to 5'-AZA treatment. Here, KLHL2 is linked to acute myeloid leukemia.