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Blood, Vol. 95 No. 1 (January 1), 2000:
pp. 320-327
Myelokathexis, a congenital disorder of severe neutropenia
characterized by accelerated apoptosis and defective expression of
bcl-x in neutrophil precursors
Andrew A. G. Aprikyan,
W. Conrad Liles,
Julie R. Park,
Mechthild Jonas,
Emil Y. Chi, and
David C. Dale
From the Departments of Medicine, Pediatrics, and Pathology,
University of Washington School of Medicine, Seattle, WA.
Myelokathexis is a congenital disorder that causes severe chronic
leukopenia and neutropenia. Characteristic findings include degenerative changes and hypersegmentation of mature neutrophils and
hyperplasia of bone marrow myeloid cells. The associated neutropenia can be partially corrected by treatment with granulocyte
colony-stimulating factor (G-CSF) or granulocyte-macrophage
colony-stimulating factor (GM-CSF). These features led us to propose
that accelerated apoptosis of neutrophil precursors might account for
the neutropenic phenotype. Blood and bone marrow aspirates were
obtained from 4 patients (2 unrelated families) with myelokathexis
before G-CSF therapy and from 2 of the affected persons after
G-CSF therapy (1 µg/kg per day subcutaneously for 3 weeks). Bone
marrow was fractionated using immunomagnetic bead cell sorting into
CD34+, CD33+/CD34 , and
CD15+/CD34/CD33 cell
populations. Examination of these cells by flow cytometry and
electron microscopy revealed abundant apoptosis in the
CD15+ neutrophil precursor population, characterized by
enhanced annexin-V binding, extensive membrane blebbing, condensation
of heterochromatin, and cell fragmentation. Colony-forming assays
demonstrated significant reduction in a proportion
of bone marrow myeloid-committed progenitor cells.
Immunohistochemical analysis revealed a selective decrease in
bcl-x, but not bcl-2, expression in the
CD15+/CD34/CD33 cell
population compared with similar subpopulations of control bone
marrow-derived myeloid precursors. After G-CSF therapy, apoptotic features of patients' bone marrow cells were substantially reduced, and the absolute neutrophil counts (ANC) and expression of
bcl-x in CD15+/CD34/CD33
cells increased. The authors concluded that myelokathexis is a disease characterized by the accelerated apoptosis of granulocytes and
the depressed expression of bcl-x in bone marrow-derived
granulocyte precursor cells. These abnormalities are partially
corrected by the in vivo administration of G-CSF. (Blood.
2000;95:320-327)
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