Abnormal responses of myeloid progenitor cells to recombinant human colony-stimulating factors in congenital neutropenia

Abstract

The effects of recombinant human interleukin-3 (IL-3) and recombinant human granulocyte colony-stimulating factor (G-CSF) on the growth of myeloid progenitor cells (CFU-C) in semisolid agar culture were studied in two patients with Kostmann-type congenital neutropenia. CFU-C growth in bone marrow cells from patients was significantly reduced in response to various concentrations of either IL-3 or G-CSF alone, compared with that from normal subjects. There was no inhibitory effect of bone marrow cells from patients on normal CFU-C formation supported by IL-3 or G-CSF. However, the simultaneous stimulation with IL-3 and G- CSF induced the increase of CFU-C formation in patients with congenital neutropenia. Furthermore, CFU-C growth in both patients was supported when bone marrow cells were preincubated with IL-3 in liquid culture followed by the stimulation with G-CSF in semisolid agar culture. In contrast, that was not supported by the preincubation with G-CSF and the subsequent stimulation with IL-3. This evidence suggests that the hematopoietic progenitor cells in patients with congenital neutropenia have the potential for developing CFU-C in the combined stimulation with IL-3 and G-CSF, and that this growth may be dependent on the priming of IL-3 followed by the stimulation with G-CSF. The level of mature neutrophils in peripheral blood was not fully restored to normal levels by the daily administration of G-CSF in doses of 100 to 200 micrograms/m2 of body surface area for 20 to 25 days in both patients. These observations raise the possibility that the combination of IL-3 and G-CSF might have a potential role for the increase of neutrophil counts in patients with congenital neutropenia.

Combined corticosteroid/granulocyte colony-stimulating factor (G-CSF) therapy in the treatment of severe congenital neutropenia unresponsive to G-CSF

“…The complete etiology of the syndrome is still unclear, although autosomal-recessive inheritance has been suggested for a subgroup of these patients [4], while acquired G-CSF receptor mutations have been implicated in another cohort [5,6]. In addition, myeloid progenitor cells from SCN patients frequently show reduced in vitro responsiveness to granulocyte colony-stimulating factor (G-CSF) [7,8]. However, more than 90% of these patients respond to G-CSF therapy with increased bone marrow production of neutrophils and amelioration of the infection complications [8][9][10].…”

Cellular and molecular abnormalities in severe congenital neutropenia predisposing to leukemia

“…This term refers to the lack of cells beyond the promyelocyte stage of development in the marrow. Marrow culture studies generally have indicated that precursor cells from most of these patients retain some capacity to proliferate and form mature neutrophils [9][10][11][12], suggesting that no intrinsic defect in maturation, a characteristic of the acute myelogenous leukemia, is present in SCN [13,14]. In vitro assays have also failed to show a qualitative defect in the responsiveness of precursor cells to specific stimulators (e.g., G-CSF, GM-CSF, IL-3, kit ligand, etc.)…”

Mutations of the granulocyte‐colony stimulating factor receptor in patients with severe congenital neutropenia are not required for transformation to acute myeloid leukaemia and may be a bystander phenomenon

“…Although most patients with SCN respond to G‐CSF treatment, in order to induce a response many of them require considerably higher doses than is necessary in other neutropenic situations ( Imashuku et al , 1992 ; Dale et al , 1993 ). In vitro studies have also shown a relative resistance to G‐CSF of progenitor cells from SCN patients ( Kobayashi et al , 1990 ; Hestal et al , 1993 ) raising the possibility of a partial defect in the G‐CSF signal transduction pathway. Several groups have demonstrated that patients with SCN are able to produce normal or elevated levels of functionally normal G‐CSF ( Mempel et al , 1991 ; Pietsch et al , 1991 ; Bernhardt et al , 1993 ; Guba et al , 1994 ) and neutrophils from patients with SCN have also been shown to express normal numbers of G‐CSF receptors (G‐CSFR) with similar binding affinities to control cells ( Kyas et al , 1992 ).…”