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An activating mutation in the CSF3R gene induces a hereditary chronic neutrophilia.

Plo I, Zhang Y, Le Couédic JP, Nakatake M, Boulet JM, Itaya M, Smith SO, Debili N, Constantinescu SN, Vainchenker W, Louache F, de Botton S - J. Exp. Med. (2009)

Bottom Line: This T617N mutation energetically favors dimerization of the granulocyte colony-stimulating factor (G-CSF) receptor transmembrane domain, and thus, strongly promotes constitutive activation of the receptor and hypersensitivity to G-CSF for proliferation and differentiation, which ultimately leads to chronic neutrophilia.The survey of 12 affected individuals during three generations indicates that only one patient had a myelodysplastic syndrome.Our data thus indicate that mutations in the CSF3R gene can be responsible for hereditary neutrophilia mimicking a myeloproliferative disorder.

View Article: PubMed Central - PubMed

Affiliation: Research Laboratory on Hematopoiesis and Normal and Leukemic Stem Cells, U790, Institut National de la Santé et de la Recherche Médicale, 94805 Villejuif, France.

ABSTRACT
We identify an autosomal mutation in the CSF3R gene in a family with a chronic neutrophilia. This T617N mutation energetically favors dimerization of the granulocyte colony-stimulating factor (G-CSF) receptor transmembrane domain, and thus, strongly promotes constitutive activation of the receptor and hypersensitivity to G-CSF for proliferation and differentiation, which ultimately leads to chronic neutrophilia. Mutant hematopoietic stem cells yield a myeloproliferative-like disorder in xenotransplantation and syngenic mouse bone marrow engraftment assays. The survey of 12 affected individuals during three generations indicates that only one patient had a myelodysplastic syndrome. Our data thus indicate that mutations in the CSF3R gene can be responsible for hereditary neutrophilia mimicking a myeloproliferative disorder.

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Related in: MedlinePlus

An inherited mutation in the CSF3R gene in a familial neutrophilia. (A) Pedigree of the family. The black symbols represent affected individuals with neutrophilia and T617N amino acid substitution. The gray symbols represent individuals for whom clinical information was not available. The white symbols represent nonaffected individuals. The genotype is also indicated (N/N, normal subjects; N/M, heterozygous patients). (B) Examples of electrophoregrams from normal subjects or patient 15 DNA (T617N). (C–E) Liquid culture of CD34+ cells in the presence of SCF plus G-CSF or SCF (C and D) from controls (n = 5) or patients (n = 2, patients 7 and 15) in which three independent experiments were performed for each patient. Error bars represent means ± SD. *, P < 0.05. (E) Cytological examination at day 21 of culture. Numbers indicate the percentages of mature granulocytic cells. Results are representative of controls (n = 3) or patients (n = 2, patients 7 and 15) in which two independent experiments were performed for each patient. (F) Western blot analysis of P-Jak2, P-STAT3, P-STAT5, P-ERK p42-p44, and P-AKT antibodies in normal or patient CD34+ cells stimulated by G-CSF in the presence or not of AZ1480. Results are representative of three independent experiments either with control or patient 15. Black lines indicate that intervening lanes have been spliced out.
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fig1: An inherited mutation in the CSF3R gene in a familial neutrophilia. (A) Pedigree of the family. The black symbols represent affected individuals with neutrophilia and T617N amino acid substitution. The gray symbols represent individuals for whom clinical information was not available. The white symbols represent nonaffected individuals. The genotype is also indicated (N/N, normal subjects; N/M, heterozygous patients). (B) Examples of electrophoregrams from normal subjects or patient 15 DNA (T617N). (C–E) Liquid culture of CD34+ cells in the presence of SCF plus G-CSF or SCF (C and D) from controls (n = 5) or patients (n = 2, patients 7 and 15) in which three independent experiments were performed for each patient. Error bars represent means ± SD. *, P < 0.05. (E) Cytological examination at day 21 of culture. Numbers indicate the percentages of mature granulocytic cells. Results are representative of controls (n = 3) or patients (n = 2, patients 7 and 15) in which two independent experiments were performed for each patient. (F) Western blot analysis of P-Jak2, P-STAT3, P-STAT5, P-ERK p42-p44, and P-AKT antibodies in normal or patient CD34+ cells stimulated by G-CSF in the presence or not of AZ1480. Results are representative of three independent experiments either with control or patient 15. Black lines indicate that intervening lanes have been spliced out.

Mentions: We studied a three-generation Caucasian pedigree (aged 8–80 yr; Fig. 1 A) in which 12 out of 16 individuals (6 males and 6 females) presented with a chronic neutrophilia associated with splenomegaly. The disorder was discovered in patient 15 during a unique episode of systemic inflammatory response syndrome that combined fever, tachycardia, dyspnea, pleural and pericardial effusion, hepatosplenomegaly, and weight loss. Biological features associated increased WBC counts by 102,000 cells/mm3, with 75% segmented neutrophils and 20% immature granulocytes, the hemoglobin level by 10 g/dl, and the platelet count by 101,000 cells/mm3. BM analysis revealed an increase in granulocyte precursors without an excess of blasts. Karyotype was normal. Bcr-Abl transcripts and JAK2V617F were not detected. After this episode, patient 15 returned to chronic neutrophilia, but 18 mo later, he developed a myelodysplastic syndrome (refractory anemia with an excess of blasts type I) associating pancytopenia (hemoglobin, 8.1 g/dl; platelets, 41,000 cells/mm3; 800 polymorphs per mm3 along with 12% of circulating immature granulocytes), skin infiltration by mature granulocytes, and 9% BM blasts. BM aspirate examination also showed a marked dysgranulopoiesis but no dyserythropoiesis or dysmegakaryopoiesis. A clonal abnormality (del 3q26) was detected by a conventional cytogenetic in 70% of the metaphases (14 out of 20). A fluorescent in situ hybridization analysis did not show evidence of EVI1 rearrangement (De Melo et al., 2008). To eliminate a transcriptional activation of EVI1, we performed quantitative real-time PCR (qRT-PCR). A 30% decrease in EVI1 mRNA was detected (Fig. S1), suggesting that the deletion includes this gene.


An activating mutation in the CSF3R gene induces a hereditary chronic neutrophilia.

Plo I, Zhang Y, Le Couédic JP, Nakatake M, Boulet JM, Itaya M, Smith SO, Debili N, Constantinescu SN, Vainchenker W, Louache F, de Botton S - J. Exp. Med. (2009)

An inherited mutation in the CSF3R gene in a familial neutrophilia. (A) Pedigree of the family. The black symbols represent affected individuals with neutrophilia and T617N amino acid substitution. The gray symbols represent individuals for whom clinical information was not available. The white symbols represent nonaffected individuals. The genotype is also indicated (N/N, normal subjects; N/M, heterozygous patients). (B) Examples of electrophoregrams from normal subjects or patient 15 DNA (T617N). (C–E) Liquid culture of CD34+ cells in the presence of SCF plus G-CSF or SCF (C and D) from controls (n = 5) or patients (n = 2, patients 7 and 15) in which three independent experiments were performed for each patient. Error bars represent means ± SD. *, P < 0.05. (E) Cytological examination at day 21 of culture. Numbers indicate the percentages of mature granulocytic cells. Results are representative of controls (n = 3) or patients (n = 2, patients 7 and 15) in which two independent experiments were performed for each patient. (F) Western blot analysis of P-Jak2, P-STAT3, P-STAT5, P-ERK p42-p44, and P-AKT antibodies in normal or patient CD34+ cells stimulated by G-CSF in the presence or not of AZ1480. Results are representative of three independent experiments either with control or patient 15. Black lines indicate that intervening lanes have been spliced out.
© Copyright Policy - openaccess
Related In: Results  -  Collection

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fig1: An inherited mutation in the CSF3R gene in a familial neutrophilia. (A) Pedigree of the family. The black symbols represent affected individuals with neutrophilia and T617N amino acid substitution. The gray symbols represent individuals for whom clinical information was not available. The white symbols represent nonaffected individuals. The genotype is also indicated (N/N, normal subjects; N/M, heterozygous patients). (B) Examples of electrophoregrams from normal subjects or patient 15 DNA (T617N). (C–E) Liquid culture of CD34+ cells in the presence of SCF plus G-CSF or SCF (C and D) from controls (n = 5) or patients (n = 2, patients 7 and 15) in which three independent experiments were performed for each patient. Error bars represent means ± SD. *, P < 0.05. (E) Cytological examination at day 21 of culture. Numbers indicate the percentages of mature granulocytic cells. Results are representative of controls (n = 3) or patients (n = 2, patients 7 and 15) in which two independent experiments were performed for each patient. (F) Western blot analysis of P-Jak2, P-STAT3, P-STAT5, P-ERK p42-p44, and P-AKT antibodies in normal or patient CD34+ cells stimulated by G-CSF in the presence or not of AZ1480. Results are representative of three independent experiments either with control or patient 15. Black lines indicate that intervening lanes have been spliced out.
Mentions: We studied a three-generation Caucasian pedigree (aged 8–80 yr; Fig. 1 A) in which 12 out of 16 individuals (6 males and 6 females) presented with a chronic neutrophilia associated with splenomegaly. The disorder was discovered in patient 15 during a unique episode of systemic inflammatory response syndrome that combined fever, tachycardia, dyspnea, pleural and pericardial effusion, hepatosplenomegaly, and weight loss. Biological features associated increased WBC counts by 102,000 cells/mm3, with 75% segmented neutrophils and 20% immature granulocytes, the hemoglobin level by 10 g/dl, and the platelet count by 101,000 cells/mm3. BM analysis revealed an increase in granulocyte precursors without an excess of blasts. Karyotype was normal. Bcr-Abl transcripts and JAK2V617F were not detected. After this episode, patient 15 returned to chronic neutrophilia, but 18 mo later, he developed a myelodysplastic syndrome (refractory anemia with an excess of blasts type I) associating pancytopenia (hemoglobin, 8.1 g/dl; platelets, 41,000 cells/mm3; 800 polymorphs per mm3 along with 12% of circulating immature granulocytes), skin infiltration by mature granulocytes, and 9% BM blasts. BM aspirate examination also showed a marked dysgranulopoiesis but no dyserythropoiesis or dysmegakaryopoiesis. A clonal abnormality (del 3q26) was detected by a conventional cytogenetic in 70% of the metaphases (14 out of 20). A fluorescent in situ hybridization analysis did not show evidence of EVI1 rearrangement (De Melo et al., 2008). To eliminate a transcriptional activation of EVI1, we performed quantitative real-time PCR (qRT-PCR). A 30% decrease in EVI1 mRNA was detected (Fig. S1), suggesting that the deletion includes this gene.

Bottom Line: This T617N mutation energetically favors dimerization of the granulocyte colony-stimulating factor (G-CSF) receptor transmembrane domain, and thus, strongly promotes constitutive activation of the receptor and hypersensitivity to G-CSF for proliferation and differentiation, which ultimately leads to chronic neutrophilia.The survey of 12 affected individuals during three generations indicates that only one patient had a myelodysplastic syndrome.Our data thus indicate that mutations in the CSF3R gene can be responsible for hereditary neutrophilia mimicking a myeloproliferative disorder.

View Article: PubMed Central - PubMed

Affiliation: Research Laboratory on Hematopoiesis and Normal and Leukemic Stem Cells, U790, Institut National de la Santé et de la Recherche Médicale, 94805 Villejuif, France.

ABSTRACT
We identify an autosomal mutation in the CSF3R gene in a family with a chronic neutrophilia. This T617N mutation energetically favors dimerization of the granulocyte colony-stimulating factor (G-CSF) receptor transmembrane domain, and thus, strongly promotes constitutive activation of the receptor and hypersensitivity to G-CSF for proliferation and differentiation, which ultimately leads to chronic neutrophilia. Mutant hematopoietic stem cells yield a myeloproliferative-like disorder in xenotransplantation and syngenic mouse bone marrow engraftment assays. The survey of 12 affected individuals during three generations indicates that only one patient had a myelodysplastic syndrome. Our data thus indicate that mutations in the CSF3R gene can be responsible for hereditary neutrophilia mimicking a myeloproliferative disorder.

Show MeSH
Related in: MedlinePlus