Alternative titles; symbols
HGNC Approved Gene Symbol: CSF2
Cytogenetic location: 5q31.1 Genomic coordinates (GRCh38): 5:132,073,789-132,076,170 (from NCBI)
Colony-stimulating factors (CSFs) are proteins necessary for the survival, proliferation, and differentiation of hematopoietic progenitor cells. The CSF2 gene encodes granulocyte/macrophage colony-stimulating factor (GM-CSF). Other cell lineage-specific CSFs include macrophage CSF (CSF1; 120420), granulocyte-CSF (CSF3; 138970), and 'multi-CSF,' or interleukin-3 (IL3; 147740).
Cantrell et al. (1985) isolated clones corresponding to the CSF2 gene from a human T lymphocyte cDNA library. The deduced 144-amino acid protein has a predicted molecular mass of 14 to 16 kD and shares approximately 54% sequence identity with the mouse protein.
Wong et al. (1985) also isolated cDNA clones for human GM-CSF.
Huebner et al. (1985) assigned the GMCSF gene to chromosome 5q21-q32 by somatic cell hybrid analysis and in situ hybridization. This is the same region as that involved in interstitial deletions in the 5q- syndrome (153550). They found a partially deleted GMCSF allele and a 5q- marker chromosome in a human promyelocytic leukemia cell line. The truncated GMCSF gene appeared to lie at the rejoining point for the interstitial deletion.
By in situ hybridization, Le Beau et al. (1986) assigned GMCSF to 5q23-q31. The gene was deleted in the 5q- chromosome from bone marrow cells of 2 patients with refractory anemia and del(5)(q15q33.3).
Pettenati et al. (1987) concluded that the order of loci from the centromere toward 5qter is CSF2, CSF1, and FMS (164770). By long-range mapping, Yang et al. (1988) demonstrated that the GMCSF and IL3 genes are separated by about 9 kilobases of DNA. They are tandemly arranged head to tail with IL3 on the 5-prime side of GMCSF. Frolova et al. (1991) studied linkage of CSF2 with a number of other expressed genes on chromosome 5. Thangavelu et al. (1992) presented a physical and genetic linkage map that encompassed 14 expressed genes and several markers located in the distal half of chromosome 5q. By fluorescence in situ hybridization, Le Beau et al. (1993) mapped the CSF2 gene to 5q31.1.
Adult-onset acquired pulmonary alveolar proteinosis (610910) is associated in most cases with serum IgG autoantibodies against CSF2, which impairs the interaction of GMCSF with its receptor. The alveolar accumulation of surfactant is primarily due to impaired alveolar macrophage function. Uchida et al. (2007) studied neutrophil (granulocyte) function in 12 patients with primary pulmonary alveolar proteinosis, 61 healthy controls, and 12 control subjects with either cystic fibrosis (219700) or end-stage liver disease. Cell culture studies showed that neutrophils from individuals with PAP had normal ultrastructure and differentiation markers but impaired basal functions and antimicrobial functions at baseline and even in response to administration of CSF2, features not observed in cells from the control groups. In vitro incubation of control cells with CSF2 autoantibodies isolated from patients with PAP reproduced the neutrophil dysfunction characteristic of PAP in a dose-dependent fashion. PAP neutrophils had normal expression of PU.1 (SPI1; 165170), a transcription factor essential for neutrophil differentiation, suggesting that GMCSF does not contribute to neutrophil differentiation. Similar results with autoantibodies were observed in wildtype mice. The findings indicated that GMCSF is an essential regulator of neutrophil function.
In studies using a highly bone-metastatic human breast cancer cell line, Park et al. (2007) found that constitutive NFKB (see 164011) activity in breast cancer cells initiated the bone resorption characteristic of osteolytic bone metastasis. A key target of NFKB was CSF2, which mediated osteolytic bone metastasis of breast cancer by stimulating osteoclast development. Immunostaining of human bone-metastatic breast tumor tissue revealed that expression of CSF2 correlated with NFKB activation. Park et al. (2007) concluded that NFKB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via CSF2.
Stanley et al. (1994) and Dranoff et al. (1994) simultaneously reported mice in which both alleles of the Csf2 gene were disabled. Csf2-null mice were viable and showed normal hematopoiesis, but developed striking pulmonary pathologic characteristics that closely resembled those of patients with pulmonary alveolar proteinosis.
LeVine et al. (1999) found that Cfs2-null mice cleared group B streptococcus (GBS) from the lungs more slowly than wildtype mice. Expression of Gmcsf in the respiratory epithelium of Cfs2-null mice improved bacterial clearance to levels greater than that in wildtype mice. In addition, acute aerosolization of Gmcsf to wildtype mice significantly enhanced clearance of GBS at 24 hours. In the knockout mice, GBS infection was associated with increased neutrophilic infiltration in lungs, whereas wildtype mice showed predominantly macrophage infiltrates. The findings suggested that absence of Gmcsf results in an abnormality in macrophage clearance of bacteria and that macrophage function is strongly influenced by Gmcsf. While phagocytosis of GBS was unaltered in the knockout mice, alveolar macrophages in these mice showed markedly decreased production of superoxide radicals and hydrogen peroxide.
Some heterozygous Nf1 (613113) mutant mice develop a myeloproliferative disorder (MPD), and adoptive transfer of Nf1-deficient fetal liver cells consistently induces this MPD. Birnbaum et al. (2000) found that irradiated Gmcsf-null mice transferred with Nf1-null hematopoietic cells did not develop MPD. However, Nf1-deficient hematopoietic cells of these animals were hypersensitive to exogenous administration of recombinant murine Gmcsf and developed MPD. The findings suggested that Gmcsf may play a central role in establishing and maintaining a myeloproliferative disorder. However, the cytokine was not absolutely essential, as some recipients of Nf1-null cells developed MPD with prolonged latency in the absence of Gmcsf.
Schweizerhof et al. (2009) presented evidence that GCSF and GMCSF mediate bone cancer pain and tumor-nerve interactions. Increased levels of both factors were detected in bone marrow lysates and adjoining connective tissue in a mouse sarcoma model of bone tumor-induced pain compared to controls. The functional receptors GCSFR (CSF3R; 138971) and GMCSFR (CSF2RA; 306250) were expressed on peripheral nerves in the bone matrix and in dorsal root ganglia. GMCSF sensitized nerves to mechanical stimuli in vitro and in vivo, potentiated CGRP (114130) release, and caused sprouting of sensory nerve endings in the skin. RNA interference of GCSF and GMCSF signaling in the mouse sarcoma model led to reduced tumor growth and nerve remodeling, and abrogated bone cancer pain.
Stock et al. (2016) studied a mouse model of Kawasaki disease (611775) induced by intraperitoneal injection of Candida albicans water soluble (CAWS) fraction that elicited, within a month, cardiac vasculitis characterized by a cellular infiltrate localizing to the aortic root and coronary arteries. They found that Gmcsf was selectively and rapidly generated by cardiac fibroblasts after CAWS injection. Gmcsf acted locally within the heart, driving local inflammatory gene expression by cardiac macrophages. The resulting cascade of inflammatory cytokine, chemokine, and adhesion molecule expression induced cardiac inflammation that could be markedly reduced by blockade of Gmcsf. Stock et al. (2016) concluded that GMCSF is an essential initiating cytokine in cardiac inflammation and may be a therapeutic target in Kawasaki disease.
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