Cellular and molecular abnormalities in severe congenital neutropenia predisposing to leukemia

Aprikyan, Andrew A.G.; Kutyavin, Tatyana; Stein, Steven; Aprikian, Pavel; Rodger, Elin; Liles, W. Conrad; Boxer, Laurence A.; Dale, David C.

doi:10.1016/s0301-472x(03)00048-1

Cited by 57 publications

(66 citation statements)

References 58 publications

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“…This mature 218 amino acid glycoprotein has a critical pathophysiolocial role in a variety of pulmonary disease, including lung cancer [11]. Recently, several studies reported association between mutations in the NE gene and two rare genetic diseases, cyclic neutropenia and severe congenital neutropenia [12][13][14][15][16][17][18][19]. There are 25 single nucleotide polymorphisms (SNPs) listed in the National Center for Biotechnology Information (NCBI)/SNP database (November 10, 2004), 13 of them are validated.…”

Section: Discussionmentioning

confidence: 99%

Polymorphisms in the promoter region of neutrophil elastase gene and lung cancer risk

et al. 2005

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SummaryThe neutrophil elastase (NE) gene encodes a powerful serine protease that is involved in the process of normal tissue turnover, natural host defense or tissue damage in acute and chronic inflammatory disorders. Furthermore, NE was suggested as one of the determinant factors of individual susceptibility to lung cancer resulting from imbalance between α1-antitrypsin (AT) and NE. To determine whether NE plays a role in risk for lung cancer, we screened polymorphisms in the promoter region of the NE gene and assessed the role of the NE polymorphisms in the risk for lung cancer. We confirmed three previously identified polymorphisms which are located at −903, −741, and extra 52 bp STS relative to the transcription initiation site. In addition, two new polymorphisms at −832 (G/T) and −789 (C/T) were identified. Their rare allelic frequencies of new polymorphism are 0.02 and 0.01, respectively, among Caucasians. The prevalence of the NE −903 (T/T) and (T/G) genotypes were 0.88 and 0.12 in controls as compared to 0.96 and 0.04 in lung cancer patients using genomic DNA isolated from 113 Caucasian lung cancer cases and 131 controls. A significant increase in lung cancer risk was observed for expected high NE activity genotypes (OR = 3.2, 95% CI = 1.02-10.3) as compared to low NE activity genotypes. These results were consistent with previous in vitro functional analysis, which reported an approximately two-fold increase enzyme expression with the −903T/−741G allele as compared to the −903G/ −741A variant. These results confirm that the NE promoter region polymorphisms may influence in risk for lung cancer.

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Section: Discussionmentioning

confidence: 99%

Polymorphisms in the promoter region of neutrophil elastase gene and lung cancer risk

et al. 2005

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“…10 Elevated apoptosis and cell-cycle arrest in the G 0 /G 1 phase have been described in promyelocytes of CN patients. [11][12][13][14] It is unclear how mutations in ELANE contribute to the failures in granulocytic differentiation, cell-cycle arrest, and elevated apoptosis. We and others have suggested activation of the unfolded protein response (UPR) by misfolded mutated NE protein in myeloid progenitors as one possible mechanism.…”

Section: Introductionmentioning

confidence: 99%

A lack of secretory leukocyte protease inhibitor (SLPI) causes defects in granulocytic differentiation

Klimenkova¹,

Ellerbeck²,

Klimiankou³

et al. 2014

Blood

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Key Points• The natural inhibitor of neutrophil elastase, SLPI, is severely reduced in severe congenital neutropenia patients.• SLPI controls myeloid differentiation by regulation of NFkB, ERK1/2:LEF-1, and c-myc activation.We identified diminished levels of the natural inhibitor of neutrophil elastase (NE), secretory leukocyte protease inhibitor (SLPI), in myeloid cells and plasma of patients with severe congenital neutropenia (CN). We further found that downregulation of SLPI in CD34 1 bone marrow (BM) hematopoietic progenitors from healthy individuals resulted in markedly reduced in vitro myeloid differentiation accompanied by cell-cycle arrest and elevated apoptosis. Reciprocal regulation of SLPI by NE is well documented, and we previously demonstrated diminished NE levels in CN patients. Here, we found that transduction of myeloid cells with wild-type NE or treatment with exogenous NE increased SLPI messenger RNA and protein levels, whereas transduction of mutant forms of NE or inhibition of NE resulted in downregulation of SLPI. An analysis of the mechanisms underlying the diminished myeloid differentiation caused by reduced SLPI levels revealed that downregulation of SLPI with short hairpin RNA (shRNA) upregulated nuclear factor kB levels and reduced phospho-extracellular signal-regulated kinase (ERK1/2)-mediated phosphorylation and activation of the transcription factor lymphoid enhancer-binding factor-1 (LEF-1). Notably, microarray analyses revealed severe defects in signaling cascades regulating the cell cycle, including c-Myc-downstream signaling, in myeloid cells transduced with SLPI shRNA. Taken together, these results indicate that SLPI controls the proliferation, differentiation, and cell cycle of myeloid cells. (Blood. 2014;123(8):1239-1249

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“…The cellular changes due to the mutations of neutrophil elastase in congenital and cyclic neutropenia are not yet clear (8)(9)(10). The mature neutrophils utilize the stored enzyme in phagolysosomes or release neutrophil elastase when the neutrophil is stimulated or has been lysed (12)(13).…”

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confidence: 99%

RT-PCR Based Mutation Detection of the Inflammatory Molecules Elastase II Gene Encoding Neutrophil Elastase in Cyclic Neutropenia Patients by Capillary Sequencing

et al. 2006

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Cyclic neutropenia is characterized by the maturation arrest of myeloid cells at the promyelocyte stage of hematopoiesis. In cyclic neutropenia, due to the disorder of neutrophil production, patients are predisposed to recurrent bacterial infections. Detected mutations in neutrophil elastase (ELA2) gene in genomic DNA of cyclic neutropenia were recently reported. Peripheral blood was obtained from 18 patients with cyclic neutropenia and 20 healthy individuals. Total RNA was isolated using RNA standard techniques from fresh separated cells by polymorphoprep. Elastase II mRNA expression was analyzed by employing reverse transcription PCR amplification using a total often specific primers. We amplified five exon of ELA2 gene separately and sequenced each exon. Mutational analysis was performed by directed capillary sequencing method. We found mutations in 15 out of 18 cyclic neutropenia patients (83%) and no mutation in 20 healthy individuals. Most of the mutations were in exon 4 and fewer mutation were found in exon 1.

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Cellular and molecular abnormalities in severe congenital neutropenia predisposing to leukemia

Cited by 57 publications

References 58 publications

Polymorphisms in the promoter region of neutrophil elastase gene and lung cancer risk

Polymorphisms in the promoter region of neutrophil elastase gene and lung cancer risk

A lack of secretory leukocyte protease inhibitor (SLPI) causes defects in granulocytic differentiation

RT-PCR Based Mutation Detection of the Inflammatory Molecules Elastase II Gene Encoding Neutrophil Elastase in Cyclic Neutropenia Patients by Capillary Sequencing

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