Nucleophosmin (NPM1 or B23.1) is a ubiquitously expressed nuclear phosphoprotein that plays key role in several cellular processes, including ribosome biogenesis, centrosome duplication, cell cycle progression, cell growth, and transformation. NPM1 is one of the most frequently mutated genes in AML. EDAG is a hematopoietic tissue-specific transcription regulator that plays a key role in maintaining the homeostasis of hematopoietic lineage commitment. In AML patients, the high expression level of EDAG is associated with poor prognosis. Our previous study suggest that EDAG is a physiological binding partner of NPM1 and regulates NPM1 protein stability, however, whether EDAG regulates NPM1 in AML patients and whether EDAG regulates NPM1 mutations remain unknown. In the present study, we found that in bone marrow CD34⁺ cells from AML patients, silencing of EDAG led to decreased protein stability of NPM1 protein and increased cell sensitivity to daunorubicin. Although EDAG failed to interact with NPMc⁺ and regulate its protein stability in normal culture condition, with leptomycin B treatment, EDAG overexpression enhanced the protein stability of NPMc⁺. In AML patients with NPMc⁺, the CD34⁺ cells were more responsive to daunorubicin treatment than the cells from AML with wild type NPM1, and silencing of EDAG weakly increased the sensitivity to daunorubicin. These results suggested a potential role of EDAG in chemotherapy of AML and the "escape" of NPMc⁺ protein from EDAG stabilization might contribute to the favorable prognosis of AML with NPMc⁺.