Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Systemic mastocytosis is a rare myeloproliferative-like disease, characterized by an abnormal proliferation of mast cells in various organs. Two types of clinical manifestations can be distinguished: those related to release of mast cell mediators release and those related to tumor proliferation involving different organs, these later defining systemic mastocytosis. Until recently, treatment was mainly symptomatic, without anti tumor effect. These last years, advances have been made in the understanding of the disease with the discovery of the presence, in a number of patients, of mutations of the c-kit oncogene, coding for the receptor of the major growth factor for mast cells. These mutations induce autophosphorylation of the c-kit receptor in the absence of its ligand, the Stem Cell Factor. Based on experiences acquired in the treatment of myeloproliferative disorders, evaluation of new therapeutics, such as cladribine or interferon-alpha, is in progress. Finally, it would be possible to design, in the very next future, new tyrosine kinase inhibitors targeting specifically the mutant forms of c-Kit found in patients suffering from systemic mastocytosis.
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PMID:[Mastocytosis: advances in molecular diagnosis and therapeutics]. 1524 41

Mastocytosis is characterized by mast cell proliferation that may be limited to the skin (cutaneous mastocytosis) or may involve one or more extracutaneous organs, e.g., the bone marrow (systemic mastocytosis; SM). This study objective is to evaluate the features and outcome of patients referred to M. D. Anderson Cancer Center (MDACC) with SM. A search of the MDACC database from 1944 to 2002 was conducted for patients with SM and review of their clinical charts. Eighteen patients with mastocytosis were identified in the MDACC database; 15 (11 males and 4 females) had SM and available information. Two had associated myelodysplastic syndrome (MDS), and one had acute myeloid leukemia (AML). The median age was 58 years (range 31-80). Nine patients were treated with subcutaneous interferon-alpha, and only 1 experienced temporary control of the disease. Three of these patients were then treated with imatinib mesylate: transient improvement was noted in two patients. One patient underwent stem cell transplantation as first therapy and achieved complete remission; this patient had associated MDS and is now in complete remission for 8 years. The patient with associated AML was treated with high-dose cytarabine and idarubicin; he has been in complete remission for 16 months. One patient was treated with induction chemotherapy consisting of high-dose cytarabine and 2CDA but expired due to sepsis. Three patients received symptomatic therapy only; these were the only 3 patients who presented with normal blood counts. SM is rare and has no effective standard of care. Collaboration among academic centers to accrue enough patients to evaluate novel therapeutic strategies is needed.
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PMID:Management of patients with systemic mastocytosis: review of M. D. Anderson Cancer Center experience. 1549 58

Based on generally accepted criteria and the WHO-classification, a subset of patients with systemic mastocytosis (SM) have (or develop) an associated clonal hematologic non-mast cell lineage disease (SM-AHNMD). We describe a case of SM with coexisting chronic eosinophilic leukemia (SM-CEL). The patient, a 51-year-old male, was first seen in 1992 with small-sized infiltrates of spindle-shaped mast cells in his marrow, and marked eosinophilia. Retrospectively, a CHIC2 deletion and the FIP1L1/PDGFRalpha fusion gene-product were demonstrable by FISH analysis and RT-PCR, respectively. SM-associated organopathy or mediator-related symptoms were not recorded. However, the patient developed cardiomyopathy. Therapy with interferon-alpha, hydroxyurea, and corticosteroids were without effects. By contrast, therapy with imatinib was followed by a fast and sustained response with complete and stable regression of eosinophilia, drop in eosinophil cationic protein, and decrease of serum tryptase to normal levels. This case provides further evidence for the potential of co-existence of SM with a primary eosinophilic disorder (CEL) defined by the FIP1L1/PDGFRalpha fusion gene. Because of the availability of a superior targeted drug (imatinib), it is of importance to screen for FIP1L1/PDGFRalpha in suspected CEL with or without co-existing SM.
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PMID:Systemic mastocytosis (SM) associated with chronic eosinophilic leukemia (SM-CEL): detection of FIP1L1/PDGFRalpha, classification by WHO criteria, and response to therapy with imatinib. 1640 18

Systemic mastocytosis (SM) is characterized by the abnormal growth and accumulation of mast cells (MC) in one or more organs. The interaction between the cytokine stem cell factor (SCF) and its cognate receptor, the c-kit receptor tyrosine kinase (KIT), plays a central role in regulating MC growth and differentiation. Whereas germline and somatically acquired activating mutations of KIT have been identified in SM, the issue as to whether individual KIT mutation(s) are necessary and sufficient to cause MC transformation remains unclear based on currently available data. Activating mutations of platelet-derived growth factor receptor-alpha (FIP1 L1-PDGFRA) are identified in a significant number of SM cases that have associated eosinophilia. To date, as with gastrointestinal stromal tumors, activating mutations of KIT and PDGFRA appear to be alternative and mutually exclusive genetic events in SM. The World Health Organization has specified criteria for classification of SM into six major subtypes: cutaneous mastocytosis, indolent systemic mastocytosis (ISM), systemic mastocytosis with an associated clonal hematological non-mast-cell disorder (SM-AHNMD), aggressive systemic mastocytosis (ASM), mast cell leukemia, and mast cell sarcoma. The ability to molecularly classify individual SM cases based on the presence or absence of specific mutations allows for molecularly targeted therapy in a growing number of cases. Imatinib mesylate therapy might result in complete remission of SM cases with wild-type KIT, certain KIT mutations, such as F522C, or the FIP1L1-PDGFRA fusion gene, but not of D816V-KIT-bearing SM. For the latter, interferon-alpha and 2-CdA are potential first- and second-line therapeutic options. Other drugs under investigation include novel tyrosine kinase inhibitors, as well as NF-kappaB inhibitors, which might display greater selectivity towards D816V-KIT as compared to wild type KIT. The pathogenesis of mastocytosis, its major clinical subtypes, and recent treatment advances are discussed in this chapter.
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PMID:Pathogenesis, clinical features, and treatment advances in mastocytosis. 1678 90

Deregulation of the KIT receptor TK by the prevalent activation loop mutation D816V has served as a focal point in therapeutic strategies aimed curbing neoplastic mast cell growth. Perhaps the most important development in this era of targeted therapy, and certainly relevant to KIT-driven diseases like mastocytosis, is the realization that small molecule inhibitors with varied chemical structure (eg, PKC412, dasatinib, AP23464) can circumvent the resistance of TKs to first-generation agents such as imatinib. Genuine opportunity now exists to effectively treat mastocytosis, and the arsenal consists of several orally bioavailable drugs with promising preclinical activity against D816V and other KIT mutants that promote mast cell growth. Because KIT mutations may not act as fully transforming oncogenic events in SM, it is prudent to evaluate combinations of TK inhibitors with drugs with activity in mast cell disease, such as cladribine, interferon-alpha, and corticosteroids. The identification of novel "drug-able" targets within mast cells should aid in the development of complementary therapies that promote enhanced cytotoxicity of mast cells through blockade of nonredundant signaling pathways. In addition, the generation of murine models that recapitulate human mastocytosis should accelerate preclinical testing of novel agents.
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PMID:KIT mutations in mastocytosis and their potential as therapeutic targets. 1693 Dec 94

In the absence of curative options, therapy for aggressive forms of systemic mastocytosis (SM) has relied in the use of cytoreductive agents, mainly interferon-alpha (IFN-alpha) and cladribine. However, responses are transient and only occur in a subset of patients. Gain-of-function mutations at codon 816 of the KIT protooncogene lead to constitutively active Kit receptor molecules, which are central to the pathogenesis of SM. Recent advances in the understanding of the molecular underpinnings of SM have led to the development of small molecules targeting mutant Kit tyrosine kinase isoforms that significantly have widened the range of therapeutic options for patients with SM. Some of these promising agents, such as dasatinib, AMN107, and PKC412, currently are under investigation in clinical trials whereas, others are at different stages of preclinical development. In addition, monoclonal antibodies directed to neoplastic mast cell-restricted surface antigens constitute a viable option for the treatment of SM that warrants further investigation.
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PMID:Novel approaches in the treatment of systemic mastocytosis. 1694 23

Recent studies have demonstrated that mast cells not only mediate inflammatory reactions in type I allergy but also play an important role in adaptive immunity. In the present study, we investigated the effects of interferon-alpha, which shares the same receptor as IFN-beta, on human cord blood-derived mast cells. Mast cells produced TNF-alpha, and IL-10, and expressed OX40 ligand upon activation by crosslinking of FcepsilonRI. When treated with interferon-alpha, TNF-alpha production was decreased while IL-10 and TGF-beta productions were increased. Furthermore, flow cytometric analysis revealed that interferon-alpha downregulated expression OX40 ligand on mast cells which is crucial for mast cell-T cell interaction. We confirmed that the viability of mast cells was not affected by interferon-alpha treatment. Accordingly, interferon-alpha-treated mast cells induced lower levels of CD4+ T cell proliferation compared with those without interferon-alpha treatment. These results suggest that type I interferons suppress T cell immune responses through their regulatory effects on mast cells.
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PMID:Type I interferons attenuate T cell activating functions of human mast cells by decreasing TNF-alpha production and OX40 ligand expression while increasing IL-10 production. 1698 87

Hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), and mast cell disease (MCD) are all considered myeloproliferative neoplasms, and diagnosis in each instance requires bone marrow examination with cytogenetic and molecular studies. HES should be distinguished from both molecularly defined and otherwise uncategorized CEL. The genes that are mutated in molecularly defined CEL include those that encode for platelet-derived growth factor receptors A and B and for fibroblast growth factor receptor 1. Diagnosis of MCD is facilitated by tryptase immunostaining and immunophenotyping to detect abnormal CD25-positive mast cells. Mutation screening for KITD816V is also advised but is not essential for the diagnosis of MCD. Asymptomatic patients with HES and no evidence of organ damage do not necessarily require immediate therapy. The same is true for patients with indolent MCD. At present, effective cytoreductive drugs for HES include corticosteroids, interferon-alpha (IFN-alpha), and hydroxyurea, imatinib for platelet-derived growth factor receptor A or B-rearranged CEL imatinib, and for MCD IFN-alpha and cladribine. In addition, a number of new drugs are currently being tested for their safety and efficacy in all 3 disorders.
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PMID:Hypereosinophilic syndrome, chronic eosinophilic leukemia, and mast cell disease. 1803 76

Cytoreductive therapy in systemic mastocytosis (SM) includes several drugs whose individual merit has not been well characterized. We retrospectively studied 108 Mayo Clinic patients who met the 2008 WHO diagnostic criteria for SM and received at least one cytoreductive drug. The numbers of patients who were evaluable for response to treatment with interferon-alpha with or without prednisone (IFN-alpha), hydroxyurea (HU), imatinib mesylate (IM) or 2-chlorodeoxyadenosine (2-CdA) were 40, 26, 22, and 22, respectively. The corresponding overall (major) response rates, according to recently published consensus criteria, were 53% (18%), 19% (0%), 18% (9%), and 55% (37%). The respective overall response rates in indolent SM, aggressive SM and SM associated with another clonal hematological nonmast cell lineage disease (SM-AHNMD) were 60%, 60%, 45% for IFN-alpha, 0, 0, 21% for HU, 14%, 50%, 9% for IM and 56%, 50%, 55% for 2-CdA. The absence of mast cell mediator release symptoms in IFN-alpha-treated patients and presence of circulating immature myeloid cells in 2-CdA-treated patients predicted inferior response. TET2 mutational status did not influence treatment response. Although the major response rates with these four cytoreductive agents were still suboptimal and HU was mainly used in patients with SM-AHNMD, the current study favors 2-CdA or IFN-alpha as first-line current therapy in SM and identifies patients who are likely to respond to such therapy.
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PMID:Cytoreductive therapy in 108 adults with systemic mastocytosis: Outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine. 1989 32

Indolent systemic mastocytosis (SM) patients have a varied clinical presentation, ranging from predominantly cutaneous symptoms to recurrent systemic symptoms (eg, flushing, palpitations, dyspepsia, diarrhea, bone pain) that can be severe and potentially life threatening (anaphylaxis). Mastocytosis patients without skin involvement pose a diagnostic challenge; a high index of suspicion is needed in those with mast cell-degranulation symptoms, including anaphylaxis following Hymenoptera stings or other triggers. Modern-era molecular and flow-cytometric diagnostic methods are very sensitive and can detect minimal involvement of bone marrow with atypical/clonal mast cells; in some cases, full diagnostic criteria for SM are not fulfilled. An important aspect of treatment is avoidance of known symptom triggers; other treatment principles include a stepwise escalation of antimediator therapies and consideration of cytoreductive therapies for those with treatment-refractory symptoms. The perioperative management of mastocytosis patients is nontrivial; a multidisciplinary preoperative assessment, adequate premedications, and close intra- and postoperative monitoring are critical. Smoldering mastocytosis is a variant with high systemic mast cell burden. While its clinical course can be variable, there is greater potential need for cytoreductive therapies (eg, interferon-alpha, cladribine) in this setting. A systematic approach to the diagnosis and treatment of indolent SM using a case-based approach of representative clinical scenarios is presented here.
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PMID:How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage). 2342 50


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