Acute myeloid leukemia is the most common acute leukemia in adults, the barrier of refractory and drug resistance has yet to be conquered in the clinical. Abnormal gene expression and epigenetic changes play an important role in pathogenesis and treatment. A super-enhancer is an epigenetic modifier that promotes pro-tumor genes and drug resistance by activating oncogene transcription. Multi-omics integrative analysis identifies the super-enhancer-associated geneCAPGand its high expression level was correlated with poor prognosis in AML. CAPG is a cytoskeleton protein but has an unclear function in AML. Here we show the molecular function ofCAPGin regulating NF-κB signaling pathway by proteomic and epigenomic analysis. Knockdown ofCapgin the AML murine model resulted in exhausted AML cells and prolonged survival of AML mice. In conclusion, SEs-associated gene CAPG can contributes to AML progression through NF-κB.