PubMed · 17060661
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Julian P Harriss. 2006-10-24. Granulocyte colony-stimulating factor.. https://doi.org/10.1503/cmaj.1060067
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PURPOSE OF REVIEW: Severe congenital neutropenia is a heterogeneous disorder of hematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10/l. In this review we summarize our current knowledge on inheritance and pathophysiolgy of congenital neutropenia. RECENT FINDINGS: There are two major subtypes of congenital neutropenia as judged by inheritance: autosomal dominant trait defined by neutrophil elastase mutations consisting of 60% of patients and autosomal recessive trait comprising approximately 30% of patients. This genetic heterogeneity suggests that several pathologic mechanisms may lead to the same phenotype due to downregulation of common myeloid transcription factors. Lymphoid enhancer-binding factor 1 is the most promising candidate, as its abrogation together with downregulation of lymphoid enhancer-binding factor 1 target genes is compatible with this phenotype. Congenital neutropenia is considered as a preleukemic syndrome, since after 10 years of observation the cumulative incidence for leukemia is 21%. Acquired granulocyte colony-stimulating factor receptor mutations are detected in approximately 80% of congenital neutropenia patients who developed acute myeloid leukemia. SUMMARY: Congenital neutropenia is a congenital disorder of hematopoiesis inherited by autosomal dominant or recessive traits. Downregulation of lymphoid enhancer-binding factor 1 is involved in the pathophysiology of all congenital neutropenia patients. Congenital neutropenia patients with acquired granulocyte colony-stimulating factor receptor mutations define a group with high risk for development of leukemia.
The effect of protein conformation on the rate of chemical degradation is poorly understood. To address the role of structure on chemical degradation kinetics, comparative oxidation studies of methionine residues in recombinant human granulocyte colony-stimulating factor (rhG-CSF) were performed. The kinetics of oxidation of methionine residues by hydrogen peroxide (H2O2) in rhG-CSF and corresponding chemically synthesized peptides thereof was measured at different temperatures. To assess structural effects, equilibrium denaturation experiments also were conducted on rhG-CSF, yielding the free energy of unfolding as a function of temperature. A comparison of the relative rates of oxidation of methionine residues in short peptides with those of corresponding methionine residues in rhG-CSF yields an understanding of how protein tertiary structure affects oxidation reactions. For the temperature range that was studied, 4-45 degrees C, the oxidation rate constants followed an Arrhenius equation quite well, suggesting the lack of temperature-induced local structural perturbations that affect chemical degradation rates. One of the four methionine residues, Met 122, exhibited an activation energy significantly different from that of the corresponding peptide. Extrapolation of kinetic data predicts non-Arrhenius behavior around the melting temperature. Three phenomenological models based on different mechanisms are discussed, and an application to shelf life prediction of pharmaceuticals is presented.