A protease-resistant PML-RAR{alpha} has increased leukemogenic potential in a murine model of acute promyelocytic leukemia.
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.
Uy
Geoffrey L
GL
Section of Stem Cell Biology, Division of Oncology, Washington University School of Medicine, 660 S. Euclid Avenue, St Louis, MO 63110, USA.
Lane
Andrew A
AA
Welch
John S
JS
Grieselhuber
Nicole R
NR
Payton
Jacqueline E
JE
Ley
Timothy J
TJ
D000818:Animals; D015870:Gene Expression; D006801:Humans; D020014:K562 Cells; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics / Q000378:metabolism*; D019272:Leukocyte Elastase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D020298:U937 Cells
D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D019272:Leukocyte Elastase