In our on-going studies, we have found that serum tryptase appears to reflect extent of disease and to serve as a biomarker of both disease regression and progression. We are also increasing our enrollment of families with more than one affected family member in order to investigate genetic associations. We are also documenting bone marrow biopsy findings that may similarly be used to predict disease progression and may lead the way to an improved classification of pediatric onset mastocytosis. Activating mutations in codon D816 of the tyrosine kinase receptor, KIT, are found in the majority of patients with systemic mastocytosis. In a collaboration with Dr. Takemoto and his research group, we found that the transcription factor, microphthalmia-associated transcription factor (MITF), is highly expressed in bone marrow biopsies from patients with systemic mastocytosis and activating c-KIT mutations and that KIT signaling markedly up-regulates MITF protein. MITF mRNA levels did not change significantly with KIT signaling which suggested posttranscriptional regulation. An array screen from mast cells identified miR-539 and miR-381 as being down-regulated by KIT signaling and that they repressed MITF expression through conserved miRNA binding sites in the MITF 3'-untranslated region. Forced expression of these miRNAs suppressed MITF protein and inhibited colony-forming capacity of mastocytosis cell lines, supporting the conclusion that a novel regulatory pathway exists between 2 critical mast cell factors, KIT and MITF which is mediated by miRNAs.
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