Cyclic hematopoiesis (CH, also called cyclic neutropenia) is a rare hematological disorder characterized by oscillatory production of blood cells by the bone marrow. CH occurs sporadically and in families as an autosomal dominant disorder. At 21 day intervals patients regularly have severe neutropenia, fever oral pharyngeal inflammation and on occasion severe life threatening infections. The disease responds very favorably to treatment with recombinant G-CSF and analogous autosomal recessive disease occurs in grey collie dogs whose blood cells oscillate with 14-day periodicity. This group has previously characterized the clinical and physiological features of this disease and its response to treatments. In their most recent work, they found that the cellular defect and oscillations in peripheral cells are probably due to accelerated apoptosis of marrow precursors. They have also found the genetic locus for autosomal dominant cyclic hematopoiesis maps to chromosome 19 and the disease is attributable a mutation in neutrophil elastase. In this proposal we hypothesize that the mutation of neutrophil elastase, which is expressed early in the differentiation of CD34+ cells to the myeloid lineage, leads to a gain of function or an aberrant function of this protein which in turn leads to the apoptotic death of early hematopoietic cells. We propose now to characterize the mutant neutrophil elastase and its subcellular localizations, to examine the enzymatic activities of the mutant elastase, to investigate how expression of this protein leads to impaired cell survival and to determine the genes and proteins which mediate its regulatory effects on myeloid progenitor cells in this disease. This work may lead to new therapies for this specific disease and provide new insights into the role of the neutrophil specific proteases and their inhibitors in the regulation of neutrophil production and in disease causing neutropenia.
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| Dale, David C; Bolyard, Audrey Anna; Aprikyan, Andrew (2002) Cyclic neutropenia. Semin Hematol 39:89-94 |
