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Blood, 1 May 2005, Vol. 105, No. 9, pp. 3397-3404.
Prepublished online as a Blood First Edition Paper on January 18, 2005; DOI 10.1182/blood-2004-07-2618.
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PLENARY PAPERS
Aberrant subcellular targeting of the G185R neutrophil elastase mutant associated with severe congenital neutropenia induces premature apoptosis of differentiating promyelocytes
Pam Massullo,
Lawrence J. Druhan,
Bruce A. Bunnell,
Melissa G. Hunter,
John M. Robinson,
Clay B. Marsh, and
Belinda R. Avalos
From the Bone Marrow Transplant Program, Division of Hematology/Oncology, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University College of Medicine and Public Health, Columbus; Molecular, Cellular, and Developmental Biology Program, The Ohio State University; Division of Pulmonary and Critical Care Medicine, The Ohio State University; Department of Physiology and Cell Biology, The Ohio State University, Columbus; and the Department of Pharmacology, Center for Gene Therapy, Tulane University Health Sciences Center, New Orleans, LA.
Mutations in the ELA2 gene encoding neutrophil elastase (NE) are present in most patients with severe congenital neutropenia (SCN). However, the mechanisms by which these mutations cause neutropenia remain unknown. To investigate the effects of mutant NE expression on granulopoiesis, we used the HL-60 promyelocytic cell line retrovirally transduced with the G185R NE mutant that is associated with a severe SCN phenotype. We show that the mutant enzyme accelerates apoptosis of differentiating but not of proliferating cells. Using metabolic labeling, confocal immunofluorescence microscopy, and immunoblot analysis of subcellular fractions, we also demonstrate that the G185R mutant is abnormally processed and localizes predominantly to the nuclear and plasma membranes rather than to the cytoplasmic compartment observed with the wild-type (WT) enzyme. Expression of the G185R mutant appeared to alter the subcellular distribution and expression of adaptor protein 3 (AP3), which traffics proteins from the trans-Golgi apparatus to the endosome. These observations provide further insight into potential mechanisms by which NE mutations cause neutropenia and suggest that abnormal protein trafficking and accelerated apoptosis of differentiating myeloid cells contribute to the severe SCN phenotype resulting from the G185R mutation.
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