Dispensable Role of Neutrophil Elastase in Survival and Differentiation of Human Myeloid Progenitor Cells
| Autor: | Qian Si, David C. Dale, Andrew A. Aprikyan, Nara A. Markosyan, Vahagn Makaryan, Richard A. Mumford, Paul E. Finke, Salony Maniar, Kelly M. Treonze |
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| Rok vydání: | 2008 |
| Předmět: | |
| Zdroj: | Blood. 112:3561-3561 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Severe congenital neutropenia (SCN) is a rare autosomal dominant or recessive disorder with a characteristic “maturation arrest” at the promyelocytic stage of differentiation in the bone marrow and extremely low level of neutrophils in peripheral circulation. SCN patients may evolve to develop myelodysplastic syndrome and acute myeloid leukemia (MDS/AML) with ~30% cumulative incidence of leukemia. Heterozygous mutations in the neutrophil elastase (NE, ELA2) gene have been identified in most of SCN patients with acquired and autosomal dominant inheritance (Dale et al., Blood 2000). It has been reported that accelerated apoptosis of bone marrow myeloid progenitor cells is the cellular mechanism of severe neutropenia in SCN. We and others also reported that expression of mutant elastase triggers impaired cell survival in human myeloid progenitor cells (Aprikyan et al., Exp Hem 2003; Massullo et al, Blood 2005; Kollner et al, Blood 2006; Grenda et al, Blood 2007). However, it remains unclear whether the abnormal cell survival and impaired myeloid differentiation in SCN is due to the gain-of-function or dominant negative effect of mutant NE. To answer these questions, we established tet-off HL-60 human myeloid progenitor cell lines with inducible expression of mutant or normal forms of NE and examined their survival and differentiation characteristics. Induced expression of del.145–152 mutant NE resulted in a significantly increased apoptosis of myeloid cells and a characteristic block of myeloid differentiation (p0.05, n=4). In addition, the overexpression of wild type NE had no effect on differentiation capacity of myeloid progenitor cells induced into granulocytic differentiation with retinoic acid compared with control cells expressing physiological levels of endogenous NE as determined by morphological evaluation of stained cells. Furthermore, nearly complete inhibition of NE proteolytic activity in control human myeloid progenitor cells expressing endogenous elastase with a cell-penetrant small molecule inhibitor of NE (Merck, NJ) also had no significant effect and impaired neither the cell survival nor their differentiation characteristics compared with control untreated cells (p>0.05, n=3). Thus, these data demonstrate that neutrophil elastase appears to be dispensable for the formation and differentiation of HL-60 human myeloid progenitor cells and accelerated apoptosis and impaired myeloid differentiation in SCN is attributable to a gain-of-function effect of pro-apoptotic mutant elastase. These data also suggest that small molecule inhibitors of NE may represent a promising therapy in severe congenital neutropenia. |
| Databáze: | OpenAIRE |
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