Servicio General de Citometría, Centro de Investigación del Cáncer (IBMCC-CSIC/USAL and IBSAL) and Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain.
J Allergy Clin Immunol. 2013 Apr;131(4):1213-24, 1224.e1-4. doi: 10.1016/j.jaci.2012.12.674. Epub 2013 Feb 10.
Despite the fact that a great majority (>90%) of patients with systemic mastocytosis (SM) carry a common genetic lesion, the D816V KIT mutation, little is known regarding the molecular and biological pathways underlying the clinical heterogeneity of the disease.
We sought to analyze the gene expression profile (GEP) of bone marrow mast cells (BMMCs) in patients with SM and its association with distinct clinical variants of the disease.
GEP analyses were performed by using DNA-oligonucleotide microarrays in highly purified BMMCs from patients with SM carrying the D816V KIT mutation (n=26) classified according to the diagnostic subtype of SM versus normal/reactive BMMCs (n=7). Validation of GEP results was performed with flow cytometry in the same set of samples and in an independent cohort of 176 subjects.
Overall, 758 transcripts were significantly deregulated in patients with SM, with a common GEP (n=398 genes) for all subvariants of SM analyzed. These were characterized by upregulation of genes involved in the innate and inflammatory immune response, including interferon-induced genes and genes involved in cellular responses to viral antigens, together with complement inhibitory molecules and genes involved in lipid metabolism and protein processing. Interestingly, aggressive SM additionally showed deregulation of apoptosis and cell cycle-related genes, whereas patients with indolent SM displayed increased expression of adhesion-related molecules.
BMMCs from patients with different clinical subtypes of SM display distinct GEPs, which might reflect new targetable pathways involved in the pathogenesis of the disease.
尽管绝大多数（>90%）系统性肥大细胞增多症（SM）患者携带常见的遗传病变，即 D816V KIT 突变，但对于导致该疾病临床异质性的分子和生物学途径知之甚少。
我们旨在分析 SM 患者骨髓肥大细胞（BMMC）的基因表达谱（GEP）及其与该疾病不同临床变异型的关联。
通过使用高度纯化的 SM 患者 BMMC 中的 DNA-寡核苷酸微阵列进行 GEP 分析，这些患者携带 D816V KIT 突变，并根据 SM 的诊断亚型与正常/反应性 BMMC（n=7）进行分类。在相同的样本集和 176 例独立队列中使用流式细胞术验证 GEP 结果。
总体而言，SM 患者中有 758 个转录本显著失调，所有分析的 SM 亚变异型均具有共同的 GEP（n=398 个基因）。这些基因参与先天和炎症免疫反应，包括干扰素诱导的基因和涉及细胞对病毒抗原反应的基因，以及补体抑制分子和涉及脂质代谢和蛋白质加工的基因。有趣的是，侵袭性 SM 还表现出与凋亡和细胞周期相关基因的失调，而惰性 SM 患者则表现出与粘附相关分子表达增加。
不同临床亚型 SM 患者的 BMMC 显示出不同的 GEP，这可能反映了疾病发病机制中涉及的新的可靶向途径。
