Nucleophosmin (NPM1) is either frequently mutated or subjected to chromosomal translocation in acute myeloid leukemia (AML). NPM protein is primarily located in the nucleus, but the recurrent NPMc+ mutation is characterized by cytoplasmic localization and leukemogenic properties. Similarly, the NPM-MLF1 translocation product favors the partial cytoplasmic retention of NPM. Regardless of their common cellular distribution, NPM-MLF1 malignancies engender different effects on hematopoiesis compared to NPMc+ counterparts, highlighting possible aberrant nuclear function(s) of NPM in NPMc+ and NPM-MLF1 AML. We performed a proteomics analysis and found that NPM and NPM-MLF1 interact with chromatin remodeling complexes of the ISWI family, as well as with NuRD and P/BAF complexes. Accordingly, NPM and NPM-MLF1 are recruited to transcriptionally active or repressed genes along with NuRD and P/BAF elements. Although the overall gene expression program in NPM knockdown cells is similar to that resulting from NPMc+ and is consistent with loss of nuclear function of NPM, NPM-MLF1 expression differentially altered gene transcription regulated by NPM. The abnormal gene regulation imposed by NPM-MLF1 is characterized by enhanced recruitment of NuRD to gene regulatory regions. Thus, different mechanisms orchestrate the deregulation of NPM function in NPMc+ -versus NPM1-MLF1- associated leukemia.