Defective Proliferation of Primitive Myeloid Progenitor Cells in Patients With Severe Congenital Neutropenia

• Published in: Blood Vol. 94; no. 12; pp. 4077 - 4083
• Main Authors: Konishi, Nakao, Kobayashi, Masao, Miyagawa, Shin-ichiro, Sato, Takashi, Katoh, Osamu, Ueda, Kazuhiro
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.12.1999; The Americain Society of Hematology
• Subjects: Acute Disease; Biological and medical sciences; Cell Division; Granulocyte Colony-Stimulating Factor - metabolism; Hematopoietic Stem Cells - pathology; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Leukopoiesis; Medical sciences; Neutropenia - blood; Neutropenia - congenital; Neutropenia - genetics; Neutropenia - pathology; Receptors, Granulocyte Colony-Stimulating Factor - genetics; Receptors, Granulocyte Colony-Stimulating Factor - metabolism; Human; Cell proliferation; Immunopathology; Leukopenia; Congenital; Pathogenesis; Infant; Hemopathy; Cell differentiation; Congenital disease; Myeloid cell; Immune deficiency; Case study; Child; Progenitor cell; Granulopoiesis; Neutropenia
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V94.12.4077

Although several mechanisms have been proposed to explain the pathophysiology of severe congenital neutropenia (SCN), the precise defect responsible for SCN remains unknown. We studied the responsiveness of primitive myeloid progenitor cells to hematopoietic factors in 4 patients with SCN. The number of granulocyte-macrophage (GM) colonies formed in patients was decreased in response to granulocyte colony-stimulating factor (G-CSF) in both serum-supplemented and serum-deprived culture. The polymerase chain reaction–single-strand conformational polymorphism analysis of the G-CSF receptor gene showed no variance in structure conformation between the 4 patients and the normal subjects. In patients with SCN, the nonadherent light density bone marrow cells and cells that were purified on the basis of the expression of CD34 and Kit receptor (CD34+/Kit+ cells) showed the reduced response to the combination of steel factor (SF), the ligand for flk2/flt3 (FL), and interleukin-3 (IL-3) with or without G-CSF in serum-deprived culture. Furthermore, when individual CD34+/Kit+ cells from patients were cultured in the presence of SF, FL, and IL-3, with or without G-CSF for 10 days, the number of clones proliferated and the number of cells per each proliferating clone was significantly less than those in normal subjects. These results suggest that primitive myeloid progenitor cells of patients with SCN have defective responsiveness to not only G-CSF, but also the early- or intermediate-acting hematopoietic factors, SF, FL, and IL-3.