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G-CSFR expression is not essential for neutrophil differentiation but for progenitor formation and emergency neutrophil responses

ABSTRACT: Severe congenital neutropenia (SCN) is a rare disorder characterized by a maturation arrest of myeloid progenitor cells in the bone marrow and severe reduction in the amount of circulating neutrophils. Loss-of-function mutations in the CSF3R (the gene encoding the granulocyte colony-stimulating factor (G-CSF) receptor) have been reported in a handful of cases. We describe two novel pedigrees with moderate neutropenia. G-CSFR immunostaining was greatly reduced on patient neutrophils. G-CSF did not prolong neutrophil survival or enhanced reactive oxygen species generation, and STAT-3 phosphorylation was absent, while neutrophils did respond to granulocyte-macrophage colony-stimulating factor (GM-CSF). Despite a lack of G-CSF signaling, morphology and cellular proteomics were normal. We suggest the major role of G-CSF is not in myeloid differentiation, but in generation of sufficient number of committed progenitor cells for neutrophil release and their survival during inflammation, which corresponds with G-CSFR expression in myeloid cell fractions from bone marrow of healthy individuals.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Neutrophil, Blood

DISEASE(S): Severe Congenital Neutropenia

SUBMITTER: Floris van Alphen

LAB HEAD: Prof. Dr. T.W. Kuijpers

PROVIDER: PXD018178 | Pride | 2020-09-25

REPOSITORIES: Pride

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Loss-of-function mutations in CSF3R cause moderate neutropenia with fully mature neutrophils: two novel pedigrees.

Sprenkeler Evelien G G EGG Tool Anton T J ATJ Kreft Iris C IC van Alphen Floris P J FPJ Seneviratne Suranjith L SL Maimaris Jesmeen J Luqmani Asad A van Leeuwen Karin K van Bruggen Robin R Burns Siobhan O SO Kuijpers Taco W TW

British journal of haematology 20200923 5

PMID: 32966608

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