Impairment of neutrophil oxidative burst in children with sickle cell disease is associated with heme oxygenase-1.

Sickle cell disease is a risk factor for invasive bacterial infections, and splenic dysfunction is believed to be the main underlying cause. We have previously shown that the liberation of heme in acute hemolysis can induce heme oxygenase-1 during granulopoiesis, impairing the ability of developing neutrophils to mount a bactericidal oxidative burst, and increasing susceptibility to bacterial infection. We hypothesized that this may also occur with the chronic hemolysis of sickle cell disease, potentially contributing to susceptibility to infections. We found that neutrophil oxidative burst activity was significantly lower in treatment-naïve children with sickle cell disease compared to age-, gender- and ethnicity-matched controls, whilst degranulation was similar. The defect in neutrophil oxidative burst was quantitatively related to both systemic heme oxygenase-1 activity (assessed by carboxyhemoglobin concentration) and neutrophil mobilization. A distinct population of heme oxygenase-1-expressing cells was present in the bone marrow of children with sickle cell disease, but not in healthy children, with a surface marker profile consistent with neutrophil progenitors (CD49d(Hi) CD24(Lo) CD15(Int) CD16(Int) CD11b(+/-)). Incubation of promyelocytic HL-60 cells with the heme oxygenase-1 substrate and inducer, hemin, demonstrated that heme oxygenase-1 induction during neutrophilic differentiation could reduce oxidative burst capacity. These findings indicate that impairment of neutrophil oxidative burst activity in sickle cell disease is associated with hemolysis and heme oxygenase-1 expression. Neutrophil dysfunction might contribute to risk of infection in sickle cell disease, and measurement of neutrophil oxidative burst might be used to identify patients at greatest risk of infection, who might benefit from enhanced prophylaxis

The role of mesenchymal stem cells in fetal haemopoiesis

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Managing children with chronic myeloid leukaemia (CML) Recommendations for the management of CML in children and young people up to the age of 18 years

Chronic myeloid leukaemia in children and young people is a relatively rare form of leukaemia that shows increased incidence with age and some evidence suggests that the molecular basis differs from that in adults. Significant advances in targeted therapy with the development and use in children of tyrosine kinase inhibitors and the ability to monitor and understand the prognostic significance of minimal residual disease by standardized molecular techniques has shifted the management of this condition from bone marrow transplantation as the main therapeutic modality to individualized treatment for each patient based on achieving specific milestones. The physiological changes occurring during childhood, particularly those affecting growth and development and the long-term use of treatment, pose specific challenges in this age group, which we are only beginning to understand

Exome sequencing identifies MPL as a causative gene in familial aplastic anemia

The primary cause of aplastic anemia remains unknown in many patients. The aim of this study was to clarify the genetic cause of familial aplastic anemia. Genomic DNA of an affected individual from a multiplex consanguineous family was hybridized to a Nimblegen exome library before being sequenced on a GAIIx genome analyzer. Once the disease causing homozygous mutation had been confirmed in the consanguineous family, this gene was then analyzed for mutation in 33 uncharacterized index cases of aplastic anemia (<13 years) using denaturing HPLC. Abnormal traces were confirmed by direct sequencing. Exome sequencing identified a novel homozygous nonsense mutation in the thrombopoietin receptor gene MPL. An additional novel homozygous MPL mutation was identified in the screen of 33 aplastic anemia patients. This study shows for the first time a link between homozygous MPL mutations and familial aplastic anemia. It also highlights the important role of MPL in trilineage hematopoiesis