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

Kobayashi, Masao; Yumiba, Chimako; Kawaguchi, Yoshindo; Tanaka, Yoshito; Ueda, Kazuhiro; Komazawa, Y; Okada, Kiyoka

doi:10.1182/blood.v75.11.2143.2143

Cited by 38 publications

(4 citation statements)

References 34 publications

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“…Since G-CSF plays a crucial role in the stimulation of granulopoiesis (3,8), this cytokine has been widely used in the treatment of SCN (40). Although myeloid progenitor cells from SCN patients frequently show reduced responsiveness to G-CSF (41,42), treatment with pharmacological doses of G-CSF are able to restore the neutrophil count in the majority of SCN patients (33), leading to a concomitant reduction in infection-related events (33,(42)(43)(44). It has also been employed in other neutropenic conditions, including those associated with chemotherapy (45)(46)(47).…”

Section: G-csf Therapymentioning

confidence: 99%

The role of the granulocyte colony-stimulating factor receptor (G-CSF-R) in disease

Ward

2007

Front Biosci

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Granulocyte colony-stimulating factor (G-CSF) is a key regulator of granulopoiesis via stimulation of a specific cell-surface receptor, the G-CSF-R, found on hematopoietic progenitor cells as well as neutrophilic granulocytes. It is perhaps not surprising, therefore, that mutations of the G-CSF-R has been implicated in several clinical settings that affect granulocytic differentiation, particularly severe congenital neutropenia, myelodysplastic syndrome and acute myeloid leukemia. However, other studies suggest that signalling via the G-CSF-R is also involved in a range of other malignancies. This review focuses on the molecular mechanisms through which the G-CSF-R contributes to disease.

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Section: G-csf Therapymentioning

confidence: 99%

The role of the granulocyte colony-stimulating factor receptor (G-CSF-R) in disease

Ward

2007

Front Biosci

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“…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). Moreover, treatment with pharmacological doses of G-CSF is able to restore the neutrophil count in the majority of SCN patients (5)(6)(7).…”

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confidence: 99%

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

Ward

Aesch

Gits

et al. 1999

The Journal of Experimental Medicine

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Severe congenital neutropenia (SCN) is a heterogeneous condition characterized by a drastic reduction in circulating neutrophils and a maturation arrest of myeloid progenitor cells in the bone marrow. Usually this condition can be successfully treated with granulocyte colony-stimulating factor (G-CSF). Here we describe the identification of a novel point mutation in the extracellular domain of the G-CSF receptor (G-CSF-R) in an SCN patient who failed to respond to G-CSF treatment. When this mutant G-CSF-R was expressed in myeloid cells, it was defective in both proliferation and survival signaling. This correlated with diminished activation of the receptor complex as determined by signal transducer and activator of transcription (STAT) activation, although activation of STAT5 was more affected than STAT3. Interestingly, the mutant receptor showed normal affinity for ligand, but a reduced number of ligand binding sites compared with the wild-type receptor. This suggests that the mutation in the extracellular domain affects ligand–receptor complex formation with severe consequences for intracellular signal transduction. Together these data add to our understanding of the mechanisms of cytokine receptor signaling, emphasize the role of GCSFR mutations in the etiology of SCN, and implicate such mutations in G-CSF hyporesponsiveness.

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“…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 ).…”

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confidence: 99%

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

et al. 1998

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Summary. Point mutations of the granulocyte-colony stimulating factor receptor (G-CSFR) resulting in an abnormally truncated receptor have been implicated in the pathogenesis of some cases of severe congenital neutropenia (SCN) and in the transformation of SCN to acute myeloid leukaemia (AML). We report here studies in 11 patients with SCN. No mutations were detected in the one patient who developed AML indicating that development of such mutations is not a prerequisite for transformation. Truncation mutations were detected in a minor percentage of transcripts from two other patients. In one patient the mutation has been constant at a low level (5-10% of total mRNA and 2/40 myeloid colonies) for 2 years. In the other patient the mutation was acquired, remained present at low levels for nearly 3 years and then spontaneously disappeared. Both patients had polyclonal haemopoiesis. We hypothesize that these mutations do not cause SCN, are randomly acquired with the mutant clone being expanded to detectable levels by high levels of exogenous or endogenous G-CSF, and may disappear by clonal succession. In a preleukaemic marrow the mutated subclone could achieve high levels, but this does not necessarily indicate a primary role of the mutant receptor in the leukaemogenic process.

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

Cited by 38 publications

References 34 publications

The role of the granulocyte colony-stimulating factor receptor (G-CSF-R) in disease

The role of the granulocyte colony-stimulating factor receptor (G-CSF-R) in disease

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

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

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