CSF1R gene

The CSF1R gene (CSF1R stands for: Colony Stimulating Factor 1 Receptor) is a protein-coding gene localized on chromosome 5q32. Alternative splicing leads to several transcript variants. Expression of a splice variant from an LTR promoter has been found in Hodgkin's lymphoma (HL), HL cell lines and anaplastic large cell lymphomas. An important paralog of this gene is KIT.

The protein encoded by this gene is a transmembrane tyrosine kinase receptor and belongs to the CSF1/PDGF family of tyrosine protein kinase receptors. The CSF1 receptor mediates most, if not all, of the biological effects of the cytokine CSF1. Ligand binding activates the receptor kinase through a process of oligomerization and transphosphorylation.

Mutations in the CSF1R gene have been associated with a predisposition to myeloid malignancies. The first intron of this gene contains a transcriptionally inactive ribosomal protein L7, which is present as a pseudogene in the opposite orientation.

The tyrosine protein kinase encoded by this gene, acts as a cell surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic progenitor cells, especially mononuclear phagocytes such as macrophages and monocytes. Promotes the release of proinflammatory chemokines in response to IL34 and CSF1 and thus plays an important role in innate immunity and inflammatory processes. The receptor protein plays an important role in the regulation of osteoclast proliferation and differentiation, the regulation of bone resorption and is required for normal bone and tooth development. It is required for normal male and female fertility and for the normal development of the milk ducts and acinar structures in the mammary gland during pregnancy. Activates multiple signaling pathways in response to ligand binding, including the ERK1/2 and JNK signaling pathways (Wei S et al. 2010). Phosphorylates PIK3R1, PLCG2, GRB2, SLA2 and CBL. Activation of PLCG2 leads to the production of the cellular signaling molecules diacylglycerol and inositol 1,4,5-trisphosphate, which then lead to the activation of members of the protein kinase C family, in particular PRKCD. Phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, leads to activation of the AKT1 signaling pathway. Activated CSF1R also mediates the activation of the MAP kinases MAPK1/ERK2 and/or MAPK3/ERK1 as well as the SRC family kinases SRC, FYN and YES1. Activated CSF1R transmits signals via proteins that interact directly with phosphorylated tyrosine residues in its intracellular domain as well as via adapter proteins such as GRB2. Promotes activation of STAT family members STAT3, STAT5A and/or STAT5B. Promotes tyrosine phosphorylation of SHC1 and INPP5D/SHIP-1. In the central nervous system may play a role in the development of microglial macrophages (Oosterhof N et al. 2019).

Axatilimab is a CSF1R antibody used for the treatment of refractory chronic graft versus host disease (GvHD ) (Wolf et al. 2024).

Diseases associated with CSF1R include leukoencephalopathy, hereditary diffuse, with spheroids 1 and brain abnormalities, neurodegeneration and dysosteosclerosis (Leukoencephalopathy, Hereditary Diffuse, with Spheroids 1 - ^OMIM®: 221820).

1. Oosterhof N et al. (2019) Homozygous Mutations in CSF1R Cause a Pediatric-Onset Leukoencephalopathy and Can Result in Congenital Absence of Microglia. Am J Hum Genet 104:936-947.
2. Sarantopoulos S (2024) Targeting CSF1R in Chronic GVHD - Lessons in Translation. N Engl J Med 391:1053-1055.
3. Wei S et al. (2010) Functional overlap but differential expression of CSF-1 and IL-34 in their CSF-1 receptor-mediated regulation of myeloid cells. J Leukoc Biol 88:495-505.
4. Wolff D et al. (2024) AGAVE-201 Investigators. Axatilimab in Recurrent or Refractory Chronic Graft-versus-Host Disease. N Engl J Med 391:1002-1014