The Natural History of Pediatric Onset Cutaneous and Systemic Mastocytosis

在我们正在进行的研究中，我们发现血清类胰蛋白酶似乎反映了疾病的程度，并作为疾病消退和进展的生物标志物。我们还在增加有一名以上受影响家庭成员的家庭的登记人数，以便调查遗传关联。 我们还记录了骨髓活检的结果，这些结果同样可以用来预测疾病的进展，并可能导致对儿童发作性肥大细胞增多症的改进分类。 在大多数系统性肥大细胞增多症患者中，发现酪氨酸激酶受体KIT密码子D816的激活突变。在与Takemoto博士和他的研究小组的合作中，我们发现转录因子小眼炎相关转录因子(MITF)在系统性肥大细胞增多症和激活c-kit突变的患者的骨髓活检组织中高度表达，KIT信号显著上调MITF蛋白。MITF基因的表达水平与KIT信号无关，提示转录后调控。肥大细胞阵列筛选发现miR-539和miR-381受KIT信号下调，并通过MITF 3‘-非翻译区保守的miRNA结合位点抑制MITF的表达。这些miRNAs的强制表达抑制了MITF蛋白的表达，抑制了肥大细胞增殖的集落形成能力，支持了在两个关键的肥大细胞因子KIT和MITF之间存在由miRNAs介导的新的调控途径的结论。

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.