Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mastocytosis is characterized by accumulations of mast cells in various organs (1). Most cases are indolent and confined to the skin, where discrete mast cell infiltrates are associated increased epidermal melanin, a clinical picture known as urticaria pigmentosa (UP). Other forms of mastocytosis combine UP with aggressive involvement of other organs or with haemotologic abnormalities (1-4). It is not known whether all forms of mastocytosis are true neoplasms or whether some might represent reactive hyperplasias (5-7). The c-KIT proto-oncogene encodes a type III receptor tyrosine kinase (KIT) that is critical to the development and survival of mast cells and melanocytes (8-11). The ligand for KIT (KL) can stimulate mast cell development, proliferation, and mediator release (9,12-17), as well as melanocyte proliferation and pigment production (18-20). To determine the role of c-KIT in the pathogenesis of mastocytosis, we examined tissue and cells isolated from a patient with UP and aggressive systemic mastocytosis with massive splenic involvement. We found a mutation that results in constitutive activation and expression of c-KIT in mast cells of both skin and spleen. This is the first in situ demonstration of an activation c-KIT mutation in neoplastic cells. It also demonstrates the clonal and neoplastic nature of this form of mastocytes.
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PMID:Somatic c-KIT activating mutation in urticaria pigmentosa and aggressive mastocytosis: establishment of clonality in a human mast cell neoplasm. 858 24

Mastocytosis is a neoplastic disease caused at least in part by somatic mutations of the c-KIT proto-oncogene resulting in constitutive activation of its protein product, KIT, the receptor tyrosine kinase for stem cell factor. KIT stimulates mast cell proliferation and prevents apoptosis of neoplastic mast cells. To develop potential therapies for mastocytosis we used indolinones, small molecules that inhibit tyrosine kinases. Four indolinone derivatives (SU4984, SU6663, SU6577, and SU5614) inhibited wild-type KIT, but variably inhibited constitutively activated KIT mutants. SU4984, SU6577, and SU5614 were effective against KIT with juxtamembrane activating mutations, whereas only SU6577 could suppress KIT containing either juxtamembrane or kinase domain activating mutations. Furthermore, SU4984, SU6577, and SU5614 killed neoplastic mast cells expressing a juxtamembrane-mutated KIT, whereas SU4984 and SU6577 killed neoplastic mast cells expressing KIT bearing a kinase domain mutation. These data show a direct correlation between inhibition of constitutively activated KIT and the death of neoplastic mast cells, and point to specific tyrosine kinase inhibitors as a potential therapy aimed directly at a cause of mastocytosis.
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PMID:Indolinone derivatives inhibit constitutively activated KIT mutants and kill neoplastic mast cells. 1065 4

Mastocytosis is defined by a pathological increase in mast cell numbers in tissues. Recent clinical observations on rare manifestations highlight the diversity of this disease. The diagnosis is now aided by new surrogate markers. At the molecular level, recent studies have reinforced the role of activating mutations in KIT in the etiology of mastocytosis. These findings provide a conceptual basis for the development for new therapeutic strategies.
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PMID:Mastocytosis. 1196 26

Mastocytosis is associated with an activating mutation in the KIT oncoprotein (KITD816V) that results in autophosphorylation of the KIT receptor in a ligand-independent manner. This mutation is inherently resistant to imatinib and, to date, there remains no effective curative therapy for systemic mastocytosis associated with KITD816V. Dasatinib (BMS-354825) is a novel orally bioavailable SRC/ABL inhibitor that has activity against multiple imatinib-resistant BCR-ABL isoforms in vitro that is presently showing considerable promise in early-phase clinical trials of chronic myeloid leukemia (CML). Pharmacokinetic analysis suggests that high nanomolar concentrations of dasatinib can be achieved safely in humans. In this study, we demonstrate significant inhibitory activity of dasatinib against both wild-type KIT and the KITD816V mutation in the nanomolar range in in vitro and cell-based kinase assays. Additionally, dasatinib leads to growth inhibition of a KITD816V-harboring human masto-cytosis cell line. Significantly, dasatinib selectively kills primary neoplastic bone marrow mast cells from patients with systemic mastocytosis while sparing other hematopoietic cells. Computer modeling suggests that the KITD816V mutation destabilizes the inactive conformation of the KIT activation loop to which imatinib binds, but it is not predicted to impair binding of KIT by dasatinib. Based upon our results, further evaluation of dasatinib for the treatment of systemic masto-cytosis in clinical trials is warranted. Moreover, dasatinib may be of clinical utility in other disease settings driven by activating KIT mutations.
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PMID:Dasatinib (BMS-354825) inhibits KITD816V, an imatinib-resistant activating mutation that triggers neoplastic growth in most patients with systemic mastocytosis. 1643 89

Mastocytosis is a heterogeneous disorder characterised by the expansion and accumulation of mast cells in different organs and tissues. Mast cell physiology is closely dependent on activation of the stem cell factor/Kit signalling pathways and accumulating evidences confirm the physiopathological key role of activating KIT mutations (typically D816V) in mastocytosis and their relationship with the clinical manifestations of the disease. This paper reviews the most recent advances in the understanding of the molecular mechanisms associated with KIT mutations in mastocytosis, including recent data about the use of new therapies targeting the Kit molecule and its associated downstream signalling pathways.
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PMID:Recent advances in the understanding of mastocytosis: the role of KIT mutations. 1755 44

Mastocytosis is characterized by an abnormal proliferation and accumulation of mast cells (MC) in one or more organ systems. The current WHO classification discriminates cutaneous mastocytosis (CM) and various forms of systemic mastocytosis (SM). While CM usually follows a bening and often self-limiting course, SM is a persistent disease in which a somatic KIT mutation at codon 816 (i.e. D816V) is detectable in MC in at least 80% of cases. Symptoms in mastocytosis result from MC-derived mediators and, less frequently, from destructive tissue infiltration by MC. The clinical course of SM is usually indolent, but sometimes it may be highly aggressive and rapidly devastating. KIT is a transmembrane class III receptor tyrosine kinase which is required for MC growth, differentiation, and functional activation. Mutations in codon 816 of the KIT gene result in ligand-independent (constitutive) activation of KIT signaling and, thus, may play a central role in the pathogenesis of SM. Since there are no curative options, therapy for the aggressive forms of SM is based on cytoreductive agents, e.g. interferon-alpha (IFN-alpha) and cladribine. The expression of KIT in neoplastic MC has led to the development of targeted therapies using tyrosine kinase inhibitors (TKI) like STI571 (Imatinib, Gleevec). Unfortunately, the KIT mutation D816V is associated with relative resistance against STI571. However, TKIs with activity against KIT D816V-positive cells have recently been developed, and some of them (dasatinib, nilotinib/AMN107, PKC412) are already tested in phase I/II trials. In addition, non-TK KIT signaling inhibitors (e.g. geldanamycin, rapamycin) or monoclonal antibodies directed against neoplastic MC may evolve as future therapeutic options.
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PMID:[Therapeutically relevant mutations in the receptor tyrosine kinase KIT in mastocytosis]. 1831 12

Mastocytosis, an unusual disorder of bone marrow-derived, clonally transformed hematopoietic progenitor cells, exhibits a broad spectrum of clinical and morphologic features ranging from a self-limiting benign disorder (ie, juvenile cutaneous mastocytosis) to highly aggressive neoplasms like mast cell leukemia. Principally, mastocytosis should be divided in 2 main subentities: cutaneous mastocytosis and systemic mastocytosis mainly involving the bone marrow. Mastocytosis is a morphologic diagnosis and should not be diagnosed on the basis of clinical findings alone. Pathologists need to be aware of the disease and its mimickers. Application of the defined diagnostic criteria can confirm or exclude mastocytosis in most cases. Use of antibodies against tryptase, CD117 (KIT), and CD25 is recommended in every suspected case. Because most cases of systemic mastocytosis show a very low degree of infiltration of the bone marrow, antitryptase and anti-CD117 are of major importance for screening and quantification of mast cells, in particular to detect even small compact infiltrates as the only major diagnostic criterion for mastocytosis. Expression of CD25 on mast cells is defined as a minor diagnostic criterion and is usually seen only in mastocytosis but not in reactive states of mast cell hyperplasia.
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PMID:Mastocytosis: an unusual clonal disorder of bone marrow-derived hematopoietic progenitor cells. 1968 20

Mastocytosis is a myeloid neoplasm characterized by abnormal accumulation and frequent activation of mast cells (MCs) in various organs. Organ systems typically involved are the bone marrow, skin, liver and gastrointestinal tract. In most adult patients, the systemic form of mastocytosis (SM) is diagnosed, which includes an indolent subvariant, an aggressive subvariant and a leukemic subvariant, also termed MC leukemia. Whereas in pediatric mastocytosis, which is usually confined to the skin, a number of different KIT mutations and other defects may be detected, the KIT mutation D816V is detectable in most (adult) patients with SM. In a subset of these patients, additional oncogenic factors may lead to enhanced survival and growth of MCs and, thus, to advanced SM. Other factors may lead to MC activation, with consecutive anaphylactic reactions that can be severe or even fatal. Treatment of SM usually focuses on symptom relief by histamine receptor antagonists and other supportive therapy. However, in aggressive and leukemic variants, cytoreductive and targeted drugs must be applied. Unfortunately, the prognosis in these patients remains poor, even when treated with novel KIT-targeting agents, polychemotherapy or stem cell transplantation. This article provides a summary of our knowledge on the pathogenesis and on treatment options in SM.
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PMID:Pathogenesis, classification and treatment of mastocytosis: state of the art in 2010 and future perspectives. 2108 38

The introduction of JAK2 mutation testing has changed dramatically the diagnostic algorithms for myeloproliferative neoplasms (MPNs) but there is still a place for conventional cytogenetic analysis in the initial work-up of MPN cases, particularly as this group of myeloid disorders has been expanded to include chronic eosinophilic leukaemia and myeloid neoplasms with abnormalities of the PDGFRA, PDGFRB, and FGFR1 genes. Mastocytosis is also included under the umbrella of MPN but the cytogenetic abnormalities observed usually reflect any associated clonal haematological non-mast cell lineage disease.
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PMID:Cytogenetics of myeloproliferative neoplasms. 2143 36

The paper discusses the new 2008 WHO classification of myeloproliferative neoplasms (MPN) and compares it with its previous 2001 edition. The introduction of the last version of the WHO classification into clinical practice has been due to new molecular biological and histological evidence in patients with MPN. The classification contains substantial alterations made in a number of nosological entities and the new diagnostic marker for MPN - JAK2 gene mutation being proposed. Mastocytosis-specific c-KIT anomaly is identified. A new form of hematopoietic system tumors, such as myeloid and lymphoid neoplasias with eosinophilia and mutations of the PDGFR A and B and FGFR1 genes, is singled out and characterized. New differential diagnostic parameters of a histological study of bone marrow trepans in MPN are proposed.
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PMID:[Current diagnosis of myeloproliferative neoplasms (2008 WHO classification)]. 2143 18


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