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Molecular and Cellular Biology, January 2005, p. 23-33, Vol. 25, No. 1
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.1.23-33.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Neutrophil Elastase Is Important for PML-Retinoic Acid Receptor {alpha} Activities in Early Myeloid Cells

Andrew A. Lane and Timothy J. Ley*

Division of Oncology, Departments of Medicine and Genetics, Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri

Received 27 July 2004/ Returned for modification 9 September 2004/ Accepted 1 October 2004

Expression of the PML-retinoic acid receptor {alpha} (PML-RAR{alpha}) fusion protein is the initiating genetic event for acute promyelocytic leukemia (APL), but the molecular mechanisms responsible for disease initiation are not yet clear. Several observations have suggested that early myeloid cells are uniquely susceptible to transformation by PML-RAR{alpha}. Recently, we have shown that the early myeloid-specific protease neutrophil elastase is important for APL development in the mouse. To better understand the role of neutrophil elastase for the pathogenesis of APL, we examined the consequences of PML-RAR{alpha} expression in early myeloid cells with or without neutrophil elastase. We found that high-level PML-RAR{alpha} expression was associated with cellular toxicity that was dependent on the expression of neutrophil elastase; a mutant form of PML-RAR{alpha} that resisted neutrophil elastase cleavage was not toxic. When PML-RAR{alpha} was expressed at very low levels in the early myeloid cells of mice, it induced myeloid expansion and delayed myeloid maturation; neutrophil elastase was also required for these activities. The activities of PML-RAR{alpha} in early myeloid cells are therefore strongly influenced by the presence of neutrophil elastase. To assure physiologic relevance, PML-RAR{alpha} functions should be evaluated in neutrophil elastase-expressing early myeloid cells.

* Corresponding author. Mailing address: Washington University, Division of Oncology, 660 S. Euclid Ave., Campus Box 8007, St. Louis, MO 63110-1093. Phone: (314) 362-9337. Fax: (314) 362-9333. E-mail: tley{at}im.wustl.edu.

Molecular and Cellular Biology, January 2005, p. 23-33, Vol. 25, No. 1
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.1.23-33.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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