Abstract Previous studies in our laboratory demonstrated that the azurophil granule protease neutrophil elastase (NE) cleaves promyelocytic leukemia–retinoic acid receptor (PML-RAR)α (PR), the fusion protein that initiates acute promyelocytic leukemia (APL). Further, NE deficiency reduces the penetrance of APL in a murine model of this disease. We therefore predicted that NE-mediated PR cleavage might be important for its ability to initiate APL. To test this hypothesis, we generated a mouse expressing NE-resistant PR. These mice developed APL indistinguishable from wild-type PR, but with significantly reduced latency (median leukemia-free survival of 274 days vs 473 days for wild-type PR, P < .001). Resistance to proteolysis may increase the abundance of full-length PR protein in early myeloid cells, and our previous data suggested that noncleaved PR may be less toxic to early myeloid cells. Together, these effects appear to increase the leukemogenicity of NE-resistant PR, contrary to our previous prediction. We conclude that NE deficiency may reduce APL penetrance via indirect mechanisms that are still NE dependent.