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

系统性肥大细胞增多症（SM）是一种具有不同临床表现的骨髓增生性疾病，在大多数情况下与KIT中的D816V突变有关。在过去几年中，鉴定全身性肥大细胞增多症患者的KIT D816V突变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 D816V突变的患者无效。

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.