Granulopoiesis in patients with congenital neutropenia

Abstract

Granulopoiesis was investigated in five patients with congenital neutropenia (CN) (one Kostmann type, four benign forms). In semisolid agar culture, the marrow cells of all five patients produced normal numbers of CFU-c (colony-forming unit-culture). The size and classification of colonies were normal. In suspension culture in vitro with exogenous colony-stimulating factor (CSF) generated from omental-conditioned medium (OMCM), the myeloid precursors of all patients could proliferate and differentiate into normal polymorphonuclear neutrophils (PMNs). But in the absence of exogenous CSF, myeloid precursors of the patient with Kostmann-type CN did not proliferate or differentiate into PMNs at all. In the four patients with benign neutropenia, however, PMNs were found even without exogenous CSF similar to normal individuals. These results suggest that patients with CN may have normal granulopoietic stem cells with normal proliferative and differentiating capacity in response to exogenous CSF. When a small amount of normal human serum was added to normal marrow cultures stimulated by exogenous CSF, the colony growth increased in a superadditive manner. The enhancing activity of serum from neutropenic patients differed from that of normal serum. Especially, the addition of serum from the patient with Kostmann type CN to normal marrow cultures did not show this enhancement effect. The sera of patients with benign neutropenia had less enhancement effect than did normal control serum. These findings might be interpreted as showing an imbalance between CSF enhancer and inhibitors in the patients' serum.

Mutations in the Gene for the Granulocyte Colony-Stimulating–Factor Receptor in Patients with Acute Myeloid Leukemia Preceded by Severe Congenital Neutropenia

“…The bone marrow almost invariably shows an arrest of granulocytic maturation at the promyelocytic or myelocytic stage. [1][2][3][4][5][6] Patients with severe congenital neutropenia have an increased susceptibility to acute myeloid leukemia. [7][8][9][10] An abnormal response of granulocytic progenitor cells to granulocyte colony-stimulating factor (G-CSF) may play a part in the pathogenesis of severe congenital neutropenia.…”

Novel Point Mutation in the Extracellular Domain of the Granulocyte Colony-Stimulating Factor (G-Csf) Receptor in a Case of Severe Congenital Neutropenia Hyporesponsive to G-Csf Treatment

“…S evere congenital neutropenia (SCN) 1 is a heterogeneous disease state characterized by a severe reduction in circulating neutrophils ( Ͻ 0.2 ϫ 10 9 /liter), and a maturation arrest of bone marrow progenitor cells at the promyelocyte/myeloid stage (1)(2)(3). Myeloid progenitor cells from SCN patients frequently show reduced responsiveness to G-CSF in vitro (4,5).…”

Chronic Childhood Neutropenia: Studies on the in vitro Clonogenicity of Bone Marrow Myeloid Progenitors

“…In vitro studies with colony-stimulating activities (CSA) from various sources have demonstrated that a normal or near to normal number of myeloid progen itors capable of giving rise to colonies is present in a proportion of patients with both adult and childhood chronic neutropenia [2,5,6], In this study, we have in vestigated the colony-forming capacity of the bone marrow myeloid progenitors from 6 pediatric patients with chronic neutropenia. Recombinant granulocytemacrophage colony-stimulating factor (GM-CSF) or interleukin 3 (IL3) or the conditioned medium of the 5637 bladder carcinoma cell line were used as growth factors.…”