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The growth and development of mast cells is tightly regulated by the action of stem cell factor (SCF; also known as mast cell growth factor or steel factor) acting through a receptor known as KIT. Usually, mast cell growth is completely dependent on SCF: KIT is expressed on blood precursor cells and is stimulated by SCF to produce sufficient numbers of mast cells to perform their normal functions in wound healing and alerting the immune system to local infection. In other words, KIT acts like a switch that is turned on by SCF, resulting in mast cell production. When SCF levels fall, the switch is turned off. In mastocytosis the switch is stuck in the 'on' position, most often as a result of mutations in the KIT receptor itself, leading to over-production of mast cells. Apart from the relatively rare instances of familial mastocytosis, these mutations are acquired during the lifetime of affected individuals and cannot be passed onto their children. The most common KIT mutation is called D816V, which is an abbreviation for a mutation in the KIT gene resulting in the substitution the normal amino acid aspartic acid at position 816 of the KIT protein by valine. This mutation is present in >80% of cases of systemic mastocytosis and some cases with other forms of mastocytosis. Other mutations at position 816 or elsewhere in the gene are seen in some cases, but these are much less common (<5% of cases) and consequently most are not routinely tested for. Detection of D816 mutations is available at the Wessex Regional Genetics Laboratory, Salisbury. KIT mutations are not usually detectable in peripheral blood, and therefore the analysis should be performed on DNA extracted from bone marrow. However since mast cells may be confined to particular sites within the marrow, a negative test does not definitely exclude the presence of the mutation. We are currently working on developing more sensitive techniques to detect D816V in samples where the proportion of mast cells is small. Some mastocytosis patients also have elevated eosinophil counts (eosinophilia). A proportion of these cases are positive for the FIP1L1-PDGFRA fusion gene, an acquired abnormality that is more commonly associated with hypereosinophilic syndrome. Detection of FIP1L1-PDGFRA is important as positive disease is sensitive to treatment with GlivecTM (imatinib), but there is no value however is testing mastocytosis patients without persistent eosinophilia for FIP1L1-PDGFRA. Testing can be performed by the Wessex Regional Genetics Laboratory on peripheral blood or bone marrow samples. Although D816 positive disease is refractory to GlivecTM treatment, laboratory studies have indicated that the mutated KIT receptor may be inhibited with nilotinib (also known as AMN107) or SprycellTM (also known as dasatinib). Clinical trials are currently underway to determine if either of these compounds are actually beneficial to patients with mastocytosis.
Nick Cross 27th Feb 2007
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