KIT and mastocytosis

Division of Hematology, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Acta Haematologica (Impact Factor: 1.12). 07/2008; 119(4):194-8. DOI: 10.1159/000140630
Source: PubMed


KIT is a receptor tyrosine kinase that is functionally relevant for hematopoiesis, mast cell development and function, gametogenesis and melanogenesis. Normal KIT signaling requires binding to stem cell factor, and PI3K-Akt is one of the putative effector pathways. In humans, germline loss-of-function KIT mutations have been associated with piebaldism - an autosomal dominant condition characterized by depigmented patches of skin and hair. Gain-of-function KIT mutations are usually acquired and have been associated with myeloid malignancies including core binding factor acute myeloid leukemia and systemic mastocytosis (SM), germ cell tumors, gastrointestinal stromal tumors and sinonasal T cell lymphomas. KITD816V is the most prevalent KIT mutation in mast cell disease and occurs in more than 90% of the cases that fulfill the World Health Organization diagnostic criteria for SM. However, its precise pathogenetic contribution is not well understood. In clinical practice, SM is considered either indolent or aggressive depending on the respective absence or presence of symptomatic target organ dysfunction aside from skin disease. In general, conventional therapy for SM is suboptimal, and efforts are under way to develop and employ small molecule drugs that target mutant KIT.

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    • "Mature MCs typically present widespread plasma membrane processes, round nuclei, and numerous electron-dense cytoplasmic secretory granules. Growth, survival, differentiation, and homing are dependent on SCF-dependent c-kit signaling (Metcalfe et al., 1981, 1997) and accordingly, gain of functions mutations in the c-kit receptor result in mastocytosis (Lim et al., 2008; Fritsche-Polanz et al., 2010; Valent et al., 2011). "
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    ABSTRACT: Adenosine is a metabolite, which has long been implicated in a variety of inflammatory processes. Inhaled adenosine provokes bronchoconstriction in asthmatics or chronic obstructive pulmonary disease patients, but not in non-asthmatics. This hyper responsiveness to adenosine appears to be mediated by mast cell activation. These observations have marked the receptor that mediates the bronchoconstrictor effect of adenosine on mast cells (MCs), as an attractive drug candidate. Four subtypes (A1, A2a, A2b, and A3) of adenosine receptors have been cloned and shown to display distinct tissue distributions and functions. Animal models have firmly established the ultimate role of the A3 adenosine receptor (A3R) in mediating hyper responsiveness to adenosine in MCs, although the influence of the A2b adenosine receptor was confirmed as well. In contrast, studies of the A3R in humans have been controversial. In this review, we summarize data on the role of different adenosine receptors in mast cell regulation of inflammation and pathology, with a focus on the common and distinct functions of the A3R in rodent and human MCs. The relevance of mouse studies to the human is discussed.
    Preview · Article · Jun 2012 · Frontiers in Immunology
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    • "Mutations in KIT (D816V and other D816 mutations) are detected in over 90% of patients with SM, a clonal disorder of mast cells and their precursors. These result in altered tyrosine kinase signalling of the KIT receptor tyrosine kinase and constitutive activation of KIT receptor-dependent signalling pathways including the JAK- STAT and PI3K-AKT pathways, as seen with the JAK2 V617F mutation (Chian et al, 2001; Lim et al, 2008). Phosphorylated STAT5 and Akt are reported to be increased in cell lines and mouse models with the JAK2 V617F (James et al, 2005; Shide et al, 2008) and KIT D816V mutations (Chian et al, 2001; Shivakrupa et al, 2003) by Western blotting. "
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    ABSTRACT: The majority of Myeloproliferative Neoplasms (MPNs) are characterised by mutations in genes encoding molecules or receptors involved in cell signalling, the most common being the JAK2 V617F mutation. This mutation leads to ligand-independent activation of downstream signalling pathways by constitutive phosphorylation. The signalling pathways affected include the Janus kinase-signal transducers and activators of transcription (JAK-STAT) and phosphotidylinositide-3 kinase (PI3K) pathways, which regulate cell survival and apoptosis respectively. Monoclonal antibodies to phospho-STAT5 and phospho-Akt were generated and assessed by immunocytochemistry on bone marrow biopsies of MPN patients with JAK2 V617F, JAK2 exon 12, MPL exon 10 and KIT D816V mutations. JAK2 V617F mutation was associated with significantly increased levels of phosphorylated STAT5 and Akt in haemopoietic cells, most marked in megakaryocytes. In contrast, JAK2 exon 12 and MPL exon 10 mutations did not affect the level of phosphorylation. In systemic mastocytosis with KIT D618V mutation there was significantly increased expression of phosphorylated STAT5 and Akt in neoplastic mast cells although there was no change in the expression in other haemopoietic cells. JAK2 V617F is associated with upregulated phosphorylation of STAT5 and Akt in megakaryocytes, and to a lesser extent in other haemopoietic cells. Immunocytochemistry of bone marrow trephines for these phospho-proteins can be used as a supplementary diagnostic test with a high negative predictive value.
    Full-text · Article · Aug 2009 · British Journal of Haematology
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    ABSTRACT: Piebaldism is an autosomal dominant disorder characterized by congenital leukoderma, mostly affecting forehead, abdomen and knee. Previous studies have revealed that piebaldism is caused by mutations of the KIT gene, which encodes the cell surface transmembrane tyrosine kinase receptor for KIT ligand. We reported here a Chinese Han family with piebaldism, and performed mutation detection of KIT gene by direct sequencing. A novel missense mutation C58G was identified in the patients, but not in the healthy individuals from the family and 100 unrelated controls. This study contributes to the database on KIT in piebaldism and enriches the knowledge about the genotype/phenotype correlation.
    No preview · Article · Jun 2009 · Archives for Dermatological Research
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