TY - JOUR
T1 - Neutrophil elastase cleaves PML-RARα and is important for the development of acute promyelocytic leukemia in mice
AU - Lane, Andrew A.
AU - Ley, Timothy J.
N1 - Funding Information:
We thank Michael Dowle of GlaxoSmithKline for the gift of the NE inhibitor GW311616A. Dr. Robert Wilkinson and Mike Lin provided invaluable assistance for the confocal microscopy studies. Drs. Dan Link and Matt Walter provided helpful suggestions and advice. Also, we would like to thank Kelly Schrimpf, Mieke Hoock, and John Park for excellent mouse colony management and genotyping assistance. Nancy Reidelberger provided expert editorial assistance. This work was supported by National Institutes of Health grants CA83962 (T.J.L.) and T32 HLO 7088 (A.A.L.), and by the Buder Charitable Foundation and the Edward J. Bakewell, Jr. Trust (T.J.L.).
PY - 2003/10/31
Y1 - 2003/10/31
N2 - The fusion protein PML-RARα, generated by the t(15;17)(q22;q11.2) translocation associated with acute promyelocytic leukemia (APL), initiates APL when expressed in the early myeloid compartment of transgenic mice. PML-RARα is cleaved in several positions by a neutral serine protease in a human myeloid cell line; purification revealed that the protease is neutrophil elastase (NE). Immunofluorescence localization studies suggested that the cleavage of PML-RARα must occur within the cell, and perhaps, within the nucleus. The functional importance of NE for APL development was assessed in NE deficient mice. Greater than 90% of bone marrow PML-RARα cleaving activity was lost in the absence of NE, and NE (but not Cathepsin G) deficient animals were protected from APL development. Primary mouse and human APL cells also contain NE-dependent PML-RARα cleaving activity. Since NE is maximally produced in promyelocytes, this protease may play a role in APL pathogenesis by facilitating the leukemogenic potential of PML-RARα.
AB - The fusion protein PML-RARα, generated by the t(15;17)(q22;q11.2) translocation associated with acute promyelocytic leukemia (APL), initiates APL when expressed in the early myeloid compartment of transgenic mice. PML-RARα is cleaved in several positions by a neutral serine protease in a human myeloid cell line; purification revealed that the protease is neutrophil elastase (NE). Immunofluorescence localization studies suggested that the cleavage of PML-RARα must occur within the cell, and perhaps, within the nucleus. The functional importance of NE for APL development was assessed in NE deficient mice. Greater than 90% of bone marrow PML-RARα cleaving activity was lost in the absence of NE, and NE (but not Cathepsin G) deficient animals were protected from APL development. Primary mouse and human APL cells also contain NE-dependent PML-RARα cleaving activity. Since NE is maximally produced in promyelocytes, this protease may play a role in APL pathogenesis by facilitating the leukemogenic potential of PML-RARα.
UR - http://www.scopus.com/inward/record.url?scp=0345708448&partnerID=8YFLogxK
U2 - 10.1016/S0092-8674(03)00852-3
DO - 10.1016/S0092-8674(03)00852-3
M3 - Article
C2 - 14636558
AN - SCOPUS:0345708448
VL - 115
SP - 305
EP - 318
JO - Cell
JF - Cell
SN - 0092-8674
IS - 3
ER -