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Clinical relevance of point mutations in the cytoplasmic domain of the
granulocyte colony-stimulating factor receptor gene in patients with severe
congenital neutropenia
N Tidow, C Pilz, B Teichmann, A Muller-Brechlin, M Germeshausen, B Kasper, P Rauprich, KW Sykora and K Welte
Department of Pediatric Hematology and Oncology, Hannover Medical School,
Germany.
Recently, point mutations in the gene of the granulocyte colony-
stimulating factor (G-CSF) receptor have been reported in two patients with
severe congenital neutropenia who developed acute myeloid leukemia (AML).
We investigated the frequency of these specific G-CSF receptor mutations in
patients with congenital neutropenia undergoing treatment with r-metHuG-CSF
(Filgrastim) and the clinical relevance of these mutations. Nucleotides
2306 to 2561 including the critical region (nucleotides 2384-2429) from the
intracellular domain of the G-CSF receptor gene were amplified by reverse
transcriptase-polymerase chain reaction. Detection of point mutations was
performed with specific restriction enzyme analysis, as well as sequencing
of PCR products. Both genomic DNA and cDNA from neutrophils and mononuclear
cells were analyzed from 28 patients with severe congenital neutropenia.
Four of 28 patients with congenital neutropenia displayed a point mutation
in the tested cytoplasmic region of the G-CSF receptor gene. The point
mutations replace a glutamine codon by a stop codon of the G-CSF receptor
gene. Among these four congenital neutropenia patients with a mutated G-CSF
receptor, two developed AML. All four patients were investigated regularly
and no correlation between occurrence of G-CSF receptor mutation and time
or dose of r-metHuG-CSF treatment was found. No point mutations in the
G-CSF receptor critical domain could be detected in cells from the other 24
congenital neutropenia patients. Furthermore, we tested six family members
of the two patients with AML including mothers and fathers, one sister, and
one brother who suffers from congenital neutropenia, as well. All family
members displayed a normal G-CSF receptor gene. After the acquisition of
the G-CSF receptor mutations, the congenital neutropenia patients continued
to respond to G-CSF therapy with an increase in absolute neutrophils in the
peripheral blood. We conclude that the point mutations in the critical
region of the intracellular part of the G-CSF receptor occur spontaneously
and are not inherited. From our data, we suggest that the described G-CSF
receptor point mutations do not alter the response to treatment with
r-metHuG-CSF and are not the cause of severe congenital neutropenia.
Volume 89,
Issue 7,
pp. 2369-2375,
04/01/1997
Copyright © 1997 by The American Society of Hematology
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Granulocyte colony-stimulating factor receptor mutations in a patient with acute lymphoblastic leukemia secondary to severe congenital neutropenia
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Blood 2001 97: 829-830.
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