Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027947 (neutropenia)
17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Severe neutropenia is characterized by maturation arrest of myeloid cells at the promyelocyte stage of hematopoiesis. We reported that accelerated apoptosis of bone marrow myeloid progenitor cells was observed in both cyclic (CN) and severe congenital neutropenia (SCN). Short and long-term cultures of bone marrow CD34+ cells revealed reduced production of multipotent progenitors in SCN. In contrast, production of these cells was slightly elevated in CN compared with CD34+ cells from healthy volunteers. Production of myeloid-committed progenitor cells was significantly reduced in both CN and SCN. FACS analysis of CD34+ cells revealed G /G cell cycle arrest in SCN but not in CN.(0) (1) All CN patients and more than 90% of SCN patients have mutation in the neutrophil elastase (NE) gene. Molecular modeling of NE tertiary structure indicates that mutations observed in SCN are primarily located around the glycosylation sites, whereas CN mutations affect predominantly the active site. Transient expression of CN- or SCN-specific mutant NE cDNA results in impaired survival of human myeloid progenitor cells compared with control cells transfected with intact NE cDNA. We hypothesize that abnormal processing and subcellular localization of mutant NE might predetermine the etiology of cyclic or severe congenital neutropenia.
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PMID:Mutant elastase in pathogenesis of cyclic and severe congenital neutropenia. 1246 29

Two forms of inherited deficiency of neutrophil numbers are cyclic hematopoiesis and severe congenital neutropenia. In cyclic hematopoiesis, neutrophil counts oscillate opposite monocytes in a 3-week cycle. Severe congenital neutropenia consists of static neutropenia and a predisposition to myelodysplasia and acute myelogenous leukemia. All cases of cyclic neutropenia and most cases of severe congenital neutropenia result from heterozygous germline mutations in the gene encoding neutrophil elastase, ela2. Recent work extends the list of neutropenia genes to include WASp, Gfi-1, adaptin, and tafazzin. Studies of mosaic patients suggest that ela2 mutations act in a cell-autonomous fashion. A hypothetical feedback circuit potentially interconnects these genes. Genetic dissection of signaling in model organisms along with experimental hematology implicate C/EPBepsilon, RUNX1/AML1, Notch family members, LEF1, and Cdc42 as additional nodes in this pathway. The authors propose that neutrophil elastase acts as an inhibitor of myelopoiesis, substantiating a chalone hypothesis proposed many years ago.
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PMID:Role of neutrophil elastase in bone marrow failure syndromes: molecular genetic revival of the chalone hypothesis. 1248 11

Human cyclic neutropenia, also referred to as cyclic hematopoiesis, is a rare disease characterized by periodic fluctuations in blood cell production by the bone marrow and a corresponding recurrent severe neutropenia every 19-21 days. This results in bacterial infections and shortened life expectancy. Platelets, monocytes, lymphocytes, and reticulocytes cycle with the same periodicity. It has been determined that the neutrophil elastase (NE) gene is mutated in all cases of human cyclic hematopoiesis. Currently, the only animal model for this disease is the grey collie dog, in which there is a strikingly similar periodic neutropenia every 12-14 days. Towards the validation of this animal model, we have cloned and sequenced the canine NE cDNA from a normal dog.
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PMID:Cloning and sequencing of the canine neutrophil elastase cDNA. 1248 25

Severe congenital neutropenia (SCN) was originally described as an autosomal recessive disorder. Autosomal dominant and sporadic forms of the disease have subsequently been recognized. All forms of the disease are manifest by persistent severe neutropenia and recurrent bacterial infection. Cyclical neutropenia (CyN) is characterized by periodic neutropenia inter-spaced with (near) normal neutrophil counts. Recently, heterozygous mutations in the ELA2 gene encoding neutrophil elastase (NE) have been described in the majority of cases of CyN and sporadic and autosomal dominant SCN. A case of paternal mosaicism has provided genetic "proof" of the pathogenicity of such mutations, but the exact pathogenic mechanism remains elusive. This review will focus on the mosaic proof and examine possible pathogenic mechanisms. The lack of obvious associations and indeed overlap between the mutations that cause the two diseases will also be discussed. Clinically to date, the discovery of an elastase mutation has been of limited value to individual patients. However, it is hoped that further genotype/phenotype studies may improve assessment of patient prognosis.
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PMID:Neutrophil elastase mutations in congenital neutropenia. 1274 50

Severe congenital neutropenia (SCN) is a rare hematological disease characterized by a selective decrease in the level of circulating neutrophils in peripheral blood, maturation arrest at the promyelocyte stage of differentiation in the bone marrow, recurrent severe infections, and evolution to acute myelogenous leukemia (AML). Cellular and molecular studies of 12 SCN patients, including 5 patients that evolved to develop AML, revealed impaired proliferative characteristics and accelerated apoptosis of bone marrow progenitor cells in SCN compared with 11 healthy controls as demonstrated by flow cytometry analysis. Sequencing analysis revealed heterozygous deletion or substitution mutations in the neutrophil elastase (NE) gene in 9 of 12 patients but not in healthy controls. Expression of various NE mutants, but not normal NE, resulted in accelerated apoptosis of human promyelocytic HL-60 progenitor cells, similar to impaired survival observed in patients' cells. Bone marrow-derived primitive CD34(+) and CD33(+)/CD34(-) progenitor cells from SCN patients evolving to AML, all with mutations in the granulocyte colony-stimulating factor receptor (G-CSFR) gene, demonstrated normal cell survival, whereas more differentiated CD15(+)/CD33(-)/CD34(-) cells negative for mutant G-CSFR gene, continue to exhibit accelerated apoptosis. These data demonstrate that impaired survival of bone marrow myeloid progenitor cells, probably driven by expression of mutant NE, is the cellular mechanism responsible for neutropenia in SCN. Furthermore, our results suggest that acquired G-CSFR mutations may initiate signaling events that override the pro-apoptotic effect of mutant NE in primitive progenitor cells, resulting in an expansion of the abnormal AML clone.
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PMID:Cellular and molecular abnormalities in severe congenital neutropenia predisposing to leukemia. 2773 39

Mice lacking the transcriptional repressor oncoprotein Gfi1 are unexpectedly neutropenic. We therefore screened GFI1 as a candidate for association with neutropenia in affected individuals without mutations in ELA2 (encoding neutrophil elastase), the most common cause of severe congenital neutropenia (SCN; ref. 3). We found dominant negative zinc finger mutations that disable transcriptional repressor activity. The phenotype also includes immunodeficient lymphocytes and production of a circulating population of myeloid cells that appear immature. We show by chromatin immunoprecipitation, gel shift, reporter assays and elevated expression of ELA2 in vivo in neutropenic individuals that GFI1 represses ELA2, linking these two genes in a common pathway involved in myeloid differentiation.
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PMID:Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2. 1277 73

There have been many recent advances in our understanding of the molecular basis of neutropenia disorders, primarily through advances in genetic analysis of inherited disorders. Molecular and cellular studies now suggest that accelerated apoptosis of neutrophil precursors in the bone marrow is the common pathophysiologic mechanism. Severe congenital neutropenia and cyclic neutropenia, both usually inherited as autosomal-dominant disorders, are caused by mutations in the neutrophil elastase gene. Myelokathexis is attributed to the downregulation of the bcl-x protein, but the genetic basis is not yet known. The genes for several diseases with more complex phenotypes (eg, glycogen storage disease type 1b, Chediak-Higashi syndrome, Shwachman-Diamond syndrome, dyskeratosis congenita, Griscelli syndrome, Barth syndrome, and Wiskott-Aldrich syndrome) have all been identified recently. The molecular mechanisms for most acquired disorders causing neutropenia (eg, idiopathic neutropenia, pure white-cell aplasia, myelodysplasia, and aplastic anemia) are not yet known. Granulocyte colony stimulating factor (G-CSF) is effective treatment for several of these conditions. Through better understanding of these disorders, we anticipate that better treatments will be found in the future.
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PMID:Molecular basis and therapy of disorders associated with chronic neutropenia. 1290 73

Chronic neutropenia syndromes associated with bone marrow (BM) failure comprise distinct congenital and acquired hematologic disorders with varying degree of neutropenia due to decreased or ineffective BM neutrophil production. Recent evidence suggests that defective granulocytopoiesis in these neutropenia states is a consequence of accelerated apoptotic cell death of BM myeloid progenitor cells and/or their differentiated progeny. Inherited or spontaneously appearing mutations in the ELA2 gene encoding for neutrophil elastase have been implicated in the accelerated apoptotic process of the BM myeloid cells in patients with cyclic and severe congenital neutropenia. A disturbed balance between pro-apoptotic and anti-apoptotic intracellular or membrane molecules such as downregulation of the bcl-2 family members or upregulation of the death receptor Fas, have been implicated in neutropenia associated with myelokathexis, Shwachman-Diamond syndrome and acquired chronic idiopathic neutropenia of adult. In this review we summarize the available evidence suggesting that abnormally increased apoptosis and impaired proliferative and differentiating properties of neutrophil progenitor and precursor cells represent a common pathogenetic mechanism for impaired granulocytopoiesis in both acquired idiopathic and congenital neutropenia states. The underlying distinct cellular and molecular abnormalities and the role of the BM microenvironment are extensively analysed.
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PMID:The role of apoptosis in the pathophysiology of chronic neutropenias associated with bone marrow failure. 1296 40

Congenital neutropenia is strictly defined as neutropenia present at birth. However, it is more generally used to describe neutropenia secondary to inherited genetic mutations. This review will discuss the presentation of such children and the various causes of congenital neutropenia. In particular, it will focus on severe congenital neutropenia (SCN) and the recent discovery of mutations in the gene encoding neutrophil elastase in the majority of cases of SCN. The potential mechanisms of pathogenesis and of transformation to leukaemia will be discussed. Shwachman-Diamond Syndrome and other less common causes of congenital neutropenia will also be reviewed. Finally, an approach to the child with potential congenital neutropenia will be presented.
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PMID:Congenital neutropenia. 1455 75

Mutations in ELA2, encoding the human serine protease neutrophil elastase, cause cyclic and severe congenital neutropenia, and recent evidence indicates that the mutations alter the membrane trafficking of neutrophil elastase. These disorders feature impaired bone marrow production of neutrophils along with excess monocytes-terminally differentiated lineages corresponding to the two alternative fates of myeloid progenitor cells. We utilized a modified yeast two-hybrid system and identified a new, widely expressed gene, N2N, whose product is homologous to Notch2, that interacts with neutrophil elastase. N2N is a 36-kDa protein distributed throughout the cell and secreted. Its amino-terminal sequence consists of several EGF repeats identical to those of the extracellular region of Notch2, and its carboxyl terminus contains a unique 24-residue domain required for interaction with neutrophil elastase. Neutrophil elastase cleaves N2N within EGF repeats in vitro and in living cells, but the C-terminal domain retards proteolysis. In vitro, N2N represses transcriptional activities of Notch proteins. Disease-causing mutations of neutrophil elastase disrupt the interaction with N2N, impair proteolysis of N2N and Notch2, and interfere with Notch2 signaling, suggesting defective proteolysis of an inhibitory form of Notch as an explanation for the alternate switching of cell fates characteristic of hereditary neutropenia.
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PMID:A novel notch protein, N2N, targeted by neutrophil elastase and implicated in hereditary neutropenia. 1467 43


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