These are relatively rare conditions, characterized by mast cell hyperplasia in bone marrow, liver, spleen, lymph nodes, gastrointestinal tract, and skin. There is often clinical evidence of mast cell activation, including urtication, pruritus, abdominal pain, nausea, vomiting, diarrhea, bone pain, flushing, vascular instability, and headache. Mastocytosis is classified into four groups:
- Indolent forms
- Mastocytosis with associated hematological disorders, including myeloproliferative/ myelodysplastic disorders
- Aggressive mastocytosis
- Mast cell leukemia
The prognosis is good for patients with indolent mastocytosis but generally poor for the other three groups, with mast cell leukemia having the most fulminant behavior. In 1993, two activating mutations in Kit/SCF-R, D816V in exon 17 and V560G in exon 11 were reported in the human mast cell line HMC 1, which was established from a patient with mast cell leukemia. Subsequent studies confirmed the presence of these mutations, in particular D816V, in Kit/SCF-R in mast cells from patients with mastocytosis. The D816V mutation has been associated with mainly sporadic, systemic mastocytosis in adults, while the G839K mutation was reported to be typically associated with cutaneous, mainly pediatric cases. Mutations at analogous sites have been identified in mast cells and mast cell lines from other species, including mouse, rat, and dog. Mastocytosis is one of the most common tumors in dogs, is usually malignant, and as a general rule associated with Kit/SCF-R mutations. The above mutations have been identified in such cases, but the most common mutations involve exon 11 and 12, including tandem duplications and other intragenic rearrangements. The mechanisms for transformation are unknown, but it is possible that a general increase in signaling caused by the Kit/ SCF-R mutations is enough to cause mast cell transformation. Accordingly, mice reconstituted with bone marrow cells expressing another constitutively active RPTK v-ErbB, develop malignant mastocytosis with associated acute myeloid leukemia (AML) that can be transplanted to secondary recipients. The V559G and the D814V mutations in murine Kit/SCF-R cause constitutive tyrosine autophosphorylation in retrovirally transduced Ba/F3 and myeloid FDC-P1 cells, and leukemia in nude mice upon injection of the transduced cells. One study showed that in murine mast cells transfected with D816V-Kit/SCF-R there was an enhanced tyrosine phosphorylation of a 130 kDa protein and enhanced ubiquitin-mediated degradation of SHP-1, a cytoplasmic protein tyrosine phosphatase that negatively regulates Kit/SCF-R signaling. In conclusion, the D816V-Kit/SCF-R and to some extent exon 11 mutations, are recurrent mutations associated with, and supposedly causally involved in, aggressive forms of mastocytosis and mast cell leukemia.
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