Disease relevance of Mastocytosis

• Esophageal eotaxin-3 mRNA and protein levels strongly correlated with tissue eosinophilia and mastocytosis [1].
• They spontaneously developed relapsing dermatitis with mastocytosis and Th2 cytokine accumulation accompanied by systemic elevation of IgE and histamine [2].
• Mutations in the juxtamembrane domain are associated with cancers, such as gastrointestinal stromal tumors and mastocytosis, and result in constitutive activation of Kit [3].
• Gain-of-function mutations in c-kit, which appear to contribute to mast cell hyperplasia, have been detected in both limited and aggressive forms of mastocytosis, suggesting that other mutations or polymorphisms may contribute to the clinical phenotype [4].
• Substitution of valine (Val) for aspartic acid (Asp) at codon 814 constitutively activates murine c-kit receptor tyrosine kinase (KIT), and Asp816Val mutation, corresponding to murine Asp814Val mutation, is found in patients with mastocytosis and acute myelocytic leukemia [5].

Psychiatry related information on Mastocytosis

• Osteoporosis occurs in patients with rheumatoid arthritis, acromegaly, anorexia nervosa, chronic liver disease, sickle cell hemoglobinopathies, and mastocytosis [6].

High impact information on Mastocytosis

• Improved diagnosis of mastocytosis by measurement of urinary histamine metabolites [7].
• These results suggest that collaboration between IL-18-dependent and Th2 cell-dependent mastocytosis is important for prompt parasite expulsion [8].
• C57BL/6 (B6) and B6 background STAT6(-/-) mice pretreated with IL-18 plus IL-2 showed prominent intestinal mastocytosis and rapidly expelled implanted adult worms of the gastrointestinal nematode Strongyloides venezuelensis [8].
• These results demonstrate a causal link in vivo between the Asp816Val Kit mutation and MC neoplasia and suggest a basis for the clinical heterogeneity of human mastocytosis [9].
• Expression of membrane-bound SCF alone resulted in epidermal melanocytosis and melanin production, but did not by itself cause mastocytosis [10].

Chemical compound and disease context of Mastocytosis

• In this report, most mastocytosis patients with systemic disease have B12-measured tryptase levels that are elevated (> 20 ng/ml) and are at least 10-fold greater than the corresponding G5-measured tryptase level [11].
• We conclude that c-KIT somatic mutations substituting valine in position 816 of KIT are characteristic of sporadic adult mastocytosis and may cause this disease [12].
• One activating Kit mutation substitutes a valine for aspartic acid at codon 816 (D816V) and is frequently observed in human mastocytosis [13].
• Although currently available tyrosine kinase inhibitors are effective in the treatment of GISTs, there has been limited success in the treatment of mastocytosis [14].
• The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations [15].

Biological context of Mastocytosis

• Because stem cell factor (SCF), the ligand for Kit (CD117(+)), is a chemoattractant for CD117(+) cells and one feature of mastocytosis is an abnormal collection of mast cells in tissues derived from CD34(+)CD117(+) mast cell precursors, the hypothesis was considered that the D816V mutation would enhance chemotaxis of these precursor cells [16].
• Cytogenetic abnormalities and their lack of relationship to the Asp816Val c-kit mutation in the pathogenesis of mastocytosis [17].
• Elevated expression of the proto-oncogene c-kit in patients with mastocytosis [18].
• During a median follow-up period of 5.5 years, 10 patients with mastocytosis were re-examined with regard to clinical symptoms, urine histamine metabolites (U-MeImAA), bone marrow cells examined with chromosome analyses, and in vitro stem cell growth for CFU-GM [19].
• Activating point mutations in the kinase domain of c-kit (often found in mastocytosis) were not detectable [20].

Anatomical context of Mastocytosis

• In addition, neoplastic mast cells isolated from patients with mastocytosis, incubated with 17-AAG ex vivo, are selectively sensitive to the drug compared to the mononuclear fraction [14].
• Since constitutive stem cell factor expression was observed in vivo, and anti-c-Kit Abs inhibited IL-9 transgenic mastocytosis in the gut, this synergistic combination of factors is likely to be responsible for the mastocytosis observed in IL-9 transgenic mice [21].
• Indeed, IL-9t dendritic cells significantly enhanced T cell proliferation and Th2 responses and, after adoptive transfer, enhanced parasite-specific IgG1 and intestinal mastocytosis in vivo, leading to accelerated expulsion of adult worms from the intestine [22].
• To address this question, we examined bone marrow biopsy specimens in a cohort of 102 patients with mastocytosis using an antibody against HDC [23].
• PURPOSE: The presence of leukotriene D4 receptors in human detrusor myocytes and increased urinary leukotriene E4 in patients with interstitial cystitis and detrusor mastocytosis imply a role for cysteinyl containing leukotrienes as proinflammatory mediators in this disease [24].

Gene context of Mastocytosis

• Association of the Q576R polymorphism in the interleukin-4 receptor alpha chain with indolent mastocytosis limited to the skin [4].
• Studies in mice infected with the gastrointestinal nematode parasite Nippostrongylus brasiliensis demonstrated that IL-4/IL-13 activation of Stat6 suppresses development of intestinal mastocytosis and does not contribute to IL-4/IL-13 production, but is still essential for parasite expulsion [25].
• We introduced the following mutations in NTRK1 tyrosine kinase domain: (i) D668N equivalent to Met D1246N associated to HPRC; (ii) D668V modelled on Kit D816V found in mastocytosis; (iii) M688T corresponding to Ret M918T associated to the cancer syndrome MEN2B [26].
• In this study we demonstrate that IL-9 is expressed early during the Th2-type response and that its elevation in vivo results in the enhancement of intestinal mastocytosis and the production of both the immunoglobulin E (IgE) and IgG1 isotypes [27].
• No significant differences in CD63 expression were observed as regards both total and cytoplasmic CD63, except for higher CD63 levels in adult patients with mastocytosis (P = 0.05) [28].

Analytical, diagnostic and therapeutic context of Mastocytosis

• The rather high proportion of patients with elevated baseline serum tryptase levels necessitates further investigation of a possible association between mastocytosis and treatment failure of conventionally dosed VIT [29].
• We have investigated the release of histamine and eicosanoids from isolated spleen cells obtained from tissue of a mastocytosis patient undergoing therapeutic splenectomy [30].
• Association of transient dermal mastocytosis and elevated plasma tryptase levels with development of adverse reactions after treatment of onchocerciasis with ivermectin [31].
• Using quantitative competitive PCR, c-kit mRNA levels on average were found to be statistically elevated in the five patients with mastocytosis with an associated hematologic disorder and in the patient with aggressive mastocytosis as compared with controls, but not elevated in patients with indolent mastocytosis [18].
• Microdialysis of histamine in the skin of patients with mastocytosis [32].

References