A translocation in 1p13 leads to constitutional activation of Colony Stimulating Factor in a small proportion of synoviocytes in Tenosynovial Giant Cell Tumour (TGCT- previously called PVNS). They attract macrophages, which have the cognate receptor, CSF1R, leading to a proliferative state resembling a benign tumour in the synovium of joints or tendon sheath. The process can be localised, as in digits, or diffuse as in the knee.
So what happens if CSF1 is inactivated? The CSF1 receptor acts through and adaptor called DAP12 or TYROBP. This adaptor is also shared by another signalling entity called TREM2. When there is homozygous inactivation of either TREM2 or TYROBP, a condition called Nasu Hakola Disease results. This condition manifests as very early presenile dementia and bone cysts, often resulting in fractures. Death occurs around age 30.
Similarly, inactivating mutations of CSF1R results in a variant of Corticobasal Degeneration called Hereditary Diffuse Encepahalopathy with Spheroids.
Interestingly, heterozygous mutations in TREM2 leads to late onset Alzheimer's Disease.
Monoclonal Antibodies to CSF1R are in clinical trial for treating TGCT. The most well known is PLX3397 or Pexidartinib. A broader, more nonspecific inhibition is performed by the tyrosine kinase inhibitor Imatinib.
So what happens if CSF1 is inactivated? The CSF1 receptor acts through and adaptor called DAP12 or TYROBP. This adaptor is also shared by another signalling entity called TREM2. When there is homozygous inactivation of either TREM2 or TYROBP, a condition called Nasu Hakola Disease results. This condition manifests as very early presenile dementia and bone cysts, often resulting in fractures. Death occurs around age 30.
Similarly, inactivating mutations of CSF1R results in a variant of Corticobasal Degeneration called Hereditary Diffuse Encepahalopathy with Spheroids.
Interestingly, heterozygous mutations in TREM2 leads to late onset Alzheimer's Disease.
Monoclonal Antibodies to CSF1R are in clinical trial for treating TGCT. The most well known is PLX3397 or Pexidartinib. A broader, more nonspecific inhibition is performed by the tyrosine kinase inhibitor Imatinib.
