Although NPM1 gene mutations leading to aberrant cytoplasmic expression of nucleophosmin (NPMc⁺) are the most frequent genetic lesions in acute myeloid leukemia, there is yet no experimental model demonstrating their oncogenicity in vivo. We report the generation and characterization of a transgenic mouse model expressing the most frequent human NPMc⁺ mutation driven by the myeloid-specific human MRP8 promoter (hMRP8-NPMc⁺). In parallel, we generated a similar wild-type NPM trans-genic model (hMRP8-NPM). Interestingly, hMRP8-NPMc⁺ transgenic mice developed myeloproliferation in bone marrow and spleen, whereas nontransgenic littermates and hMRP8-NPM transgenic mice remained disease free. These findings provide the first in vivo evidence indicating that NPMc⁺ confers a proliferative advantage in the myeloid lineage. No spontaneous acute myeloid leukemia was found in hMPR8-NPMc⁺ or hMRP8-NPM mice. This model will also aid in the development of therapeutic regimens that specifically target NPMc⁺.