The Pathogenesis, Diagnosis, And Treatment Of Systemic Mast Cell Disorders

系统性肥大细胞增多症（SM）是一种具有多种临床表现的骨髓增生性疾病，在大多数情况下与KIT中的D816 V突变相关。在过去的几年中，系统性肥大细胞增多症患者中KIT D816 V突变的鉴定具有重要的预后意义，这主要是因为酪氨酸激酶受体抑制剂如伊马替尼的可用性。然而，伊马替尼对携带KIT D816 V突变的患者无效。 因此，我们与Deciphera Pharmaceuticals合作，评估了新型KIT开关口袋抑制剂对肥大细胞增殖和活化的影响。我们发现，具有KIT D816 V突变的肿瘤性人肥大细胞系通过诱导细胞凋亡被开关口袋抑制剂显著抑制。总的来说，开关口袋抑制剂因此可以提供治疗益处。 由于肥大细胞增多症患者的嗜酸性粒细胞有时会升高，我们与Klion博士的研究小组合作，评估了嗜酸性粒细胞增多症和/或肥大细胞增多症患者的表面和可溶性IL-5 R水平。无嗜酸性粒细胞增多的系统性肥大细胞增多症患者sIL-5 R显著升高。sIL-5 R水平与血清类胰蛋白酶和嗜酸性粒细胞活化相关。这些数据可能与使用新的治疗药物靶向IL-5及其受体的嗜酸性粒细胞增多症和/或肥大细胞增多症患者的影响。 KIT有两种主要变体，其在胞外结构域的近膜区有四个氨基酸（GNNK-或GNNK+）的差异。 使用定量实时PCR检测评估GNNK-和GNNK+转录从骨髓单个核细胞的系统性肥大细胞增多症患者，我们发现，GNNK-变异体的相对表达与肿瘤性肥大细胞的参与密切相关。使用肥大细胞转染系统，我们已经发现GNNK-变体与增加的颗粒形成、细胞生长和对酪氨酸激酶抑制剂的抗性相关。 目前正在进行研究，以更好地了解这些观察结果背后的机制。

Systemic mastocytosis (SM), a myeloproliferative disorder with variable clinical manifestations, is associated in most cases with the D816V mutation in KIT. The identification of the KIT D816V mutation in patients with systemic mastocytosis has gained a major prognostic significance in the last several years, largely because of the availability of tyrosine kinase receptor inhibitors such as imatinib. However, imatinib is ineffective in patients carrying KIT D816V mutation. In collaboration with Deciphera Pharmaceuticals, we thus evaluated novel KIT switch pocket inhibitors on mast cell proliferation and activation. We found that neoplastic human mast cell lines harboring the KIT D816V mutation were significantly inhibited by the switch pocket inhibitors through the induction of apoptosis. Overall, switch pocket inhibitors thus may provide therapeutic benefit. Because eosinophils are sometimes elevated in patients with mastocytosis, we assessed surface and soluble IL-5R levels in patients with eosinophilia and/or mastocytosis in a collaboration with Dr. Klion's research group. sIL-5R was significantly elevated in patients with systemic mastocytosis without eosinophilia. sIL-5R levels correlated with serum tryptase and eosinophil activation. These data may have implications with respect to the use of novel therapeutic agents targeting IL-5 and its receptor in patients with eosinophilia and/or mastocytosis. KIT has two major variants which differ by four amino acids (GNNK- or GNNK+) at the juxta-membrane region of the extracellular domain. Using a quantitative real-time PCR assay to assess GNNK- and GNNK+ transcripts from the bone marrow mononuclear cells of patients with systemic mastoycytosis, we found that the relative expression of the GNNK- variant strongly correlated with neoplastic mast cell involvement. Using a mast cell transfection system, we have found that he GNNK- variant is associated with increased granule formation, cellular growth and resistance to the tyrosine kinase inhibitors. Studies are underway to better understand the mechanisms behind these observations.