Elastase inhibitors as potential therapies for -associated neutropenia.

Mutations in , the gene for neutrophil elastase (NE), a protease expressed early in neutrophil development, are the most frequent cause of cyclic (CyN) and severe congenital neutropenia (SCN). We hypothesized that inhibitors of NE, acting either by directly inhibiting enzymatic activity or as chaperones for the mutant protein, might be effective as therapy for CyN and SCN. We investigated β-lactam-based inhibitors of human NE (Merck Research Laboratories, Kenilworth, NJ, USA), focusing on 1 inhibitor called MK0339, a potent, orally absorbed agent that had been tested in clinical trials and shown to have a favorable safety profile.

The cellular and molecular mechanisms for neutropenia in Barth syndrome.

Barth syndrome (BTHS), a rare, X-linked, recessive disease, is characterized by neutropenia and cardiomyopathy. BTHS is caused by loss-of-function mutations of the tafazzin (TAZ) gene. We developed a model of BTHS by transfecting human HL60 myeloid progenitor cells with TAZ-specific shRNAs.

The CXCR4 antagonist plerixafor is a potential therapy for myelokathexis, WHIM syndrome.

Mutations in CXCR4 cause severe leukopenia in myelokathexis or WHIM syndrome. Plerixafor inhibits binding of CXCR4 to its ligand CXCL12. We investigated the effects of plerixafor (0.

Cyclic neutropenia and severe congenital neutropenia in patients with a shared ELANE mutation and paternal haplotype: evidence for phenotype determination by modifying genes.

Background: Cyclic neutropenia (CN) and severe congenital neutropenia (SCN) are disorders of neutrophil production that differ markedly in disease severity. Mutations of the ELANE gene (the symbol recently replacing ELA2) are considered largely responsible for most cases of CN and SCN, but specific mutations are typically associated with one or the other.

Procedure: We performed ELANE genotyping on all individuals and paternal sperm in an SCN kindred with eight SCN progeny of a sperm donor and six different mothers.

Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia.

Severe congenital neutropenia (SCN) is a genetically heterogeneous syndrome associated with mutations of ELANE (ELA2), HAX1, GFI1, WAS, CSF3R or G6PC3. We investigated the prevalence of mutations of ELANE in a cohort of 162 SCN patients for whom blood or bone marrow samples were submitted to the North American Severe Chronic Neutropenia Tissue Repository. Mutations of ELANE were found in 90 of 162 patients (55.

Functional interaction between mutations in the granulocyte colony-stimulating factor receptor in severe congenital neutropenia.

Most severe congenital neutropenia (SCN) cases possess constitutive neutrophil elastase mutations; a smaller cohort has acquired mutations truncating the granulocyte colony-stimulating factor receptor (G-CSF-R). We have described a case with constitutive extracellular G-CSF-R mutation hyporesponsive to ligand. Here we report two independent acquired G-CSF-R truncation mutations and a novel constitutive neutrophil elastase mutation in this patient.

Neutrophil elastase mutations and risk of leukaemia in severe congenital neutropenia.

Severe congenital neutropenia (SCN) is a heterogeneous bone marrow failure syndrome predisposing to myelodysplastic syndrome and acute myeloid leukaemia (MDS/AML). We studied 82 North American and Australian SCN patients enrolled in the Severe Chronic Neutropenia International Registry who were on long-term treatment with granulocyte colony-stimulating factor and for whom the neutrophil elastase (ELA2) gene was sequenced. There was no significant difference in the risk of MDS/AML in patients with mutant versus wild-type ELA2: the respective cumulative incidences at 15 years were 36% and 25% (P = 0.

Mosaic tetraploidy and transient GFI1 mutation in a patient with severe chronic neutropenia.

This report presents the case of a 15-year-old male with severe chronic neutropenia, leukopenia, and persistent tetraploid mosaicism in the bone marrow and peripheral blood. His father had mild neutropenia and bone marrow tetraploidy. Flow cytometric analysis of DNA content peripheral blood showed tetraploidy in 20% of granulocytes and 15% of monocytes.

Neutrophil elastase and granulocyte colony-stimulating factor receptor mutation analyses and leukemia evolution in severe congenital neutropenia patients belonging to the original Kostmann family in northern Sweden.

Background And Objectives: Severe congenital neutropenia (SCN) or Kostmann syndrome was originally reported to be an autosomal recessive disease of neutrophil production causing recurrent, life-threatening infections. Mutations in the neutrophil elastase gene (ELA-2) have previously been identified in patients with sporadic or autosomal dominant SCN.

Design And Methods: We studied 14 individuals (four patients with SCN and ten close relatives) belonging to the original Kostmann family in northern Sweden for mutations in the ELA-2 and the granulocyte colony-stimulating factor (G-CSF) receptor genes.

Periodontal status in two siblings with severe congenital neutropenia: diagnosis and mutational analysis of the cases.

Background: Severe congenital neutropenia (SCN), also known as Kostmann syndrome, was originally reported as an autosomal recessive disease of neutrophil production. The disease is characterized by a maturation arrest of neutrophil precursors at the promyelocytic stage of differentiation and by extremely low levels of mature neutrophils in peripheral blood.

Methods: A 6-year-old male presented with a complaint of gingival swelling and bleeding, and swelling at the left side of his face.

Kostmann syndrome: severe congenital neutropenia associated with defective expression of Bcl-2, constitutive mitochondrial release of cytochrome c, and excessive apoptosis of myeloid progenitor cells.

Kostmann syndrome, or severe congenital neutropenia (SCN), is an autosomal recessive disorder of neutrophil production. To investigate the potential role of apoptosis in SCN, bone marrow aspirates and biopsies were obtained from 4 patients belonging to the kindred originally described by Kostmann and 1 patient with SCN of unknown inheritance. An elevated degree of apoptosis was observed in the bone marrow of these patients, and a selective decrease in B-cell lymphoma-2 (Bcl-2) expression was seen in myeloid progenitor cells.

Cellular and molecular abnormalities in severe congenital neutropenia predisposing to leukemia.

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.

Cloning and sequencing of the canine neutrophil elastase cDNA.

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.

Mutant elastase in pathogenesis of cyclic and severe congenital neutropenia.

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.

Cyclic neutropenia.

Cyclic neutropenia is a rare hematologic disorder, characterized by repetitive episodes of fever, mouth ulcers, and infections attributable to recurrent severe neutropenia. Fluctuations in blood cells are due to oscillatory production of cells by the bone marrow. Recent genetic, molecular, and cellular studies have shown that autosomal-dominant cyclic neutropenia and sporadic cases of this disease are due to a mutation in the gene for neutrophil elastase (ELA2), located at 19p13.