Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
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Systemic mastocytosis is a disease of mast cell proliferation that may be associated with hematologic disorders. There are no features on examination that allow the diagnosis of systemic disease, and mast cell-derived mediators, which may be elevated in urine or blood, may also be elevated in individuals with severe allergic disorders. Thus, the diagnosis usually depends on results of bone marrow biopsy. To facilitate evaluation, surrogate markers of the extent and severity of the disease are needed. Because of the association of mastocytosis with hematologic disease, plasma levels were measured for soluble KIT (sKIT) and soluble interleukin-2 receptor alpha chain (sCD25), which are known to be cleaved in part from the mast cell surface and are elevated in some hematologic malignancies. Results revealed that levels of both soluble receptors are increased in systemic mastocytosis. Median plasma sKIT concentrations as expressed by AU/mL (1 AU = 1.4 ng/mL) were as follows: controls, 176 (n = 60); urticaria pigmentosa without systemic involvement, 194 (n = 8); systemic indolent mastocytosis, 511 (n = 30); systemic mastocytosis with an associated hematologic disorder, 1320 (n = 7); aggressive mastocytosis, 3390 (n = 3). Plasma sCD25 levels were elevated in systemic mastocytosis; the highest levels were associated with extensive bone marrow involvement. Levels of sKIT correlated with total tryptase levels, sCD25 levels, and bone marrow pathology. These results demonstrate that sKIT and sCD25 are useful surrogate markers of disease severity in patients with mastocytosis and should aid in diagnosis, in the selection of those needing a bone marrow biopsy, and in the documentation of disease progression. (Blood. 2000;96:1267-1273)
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PMID:Soluble stem cell factor receptor (CD117) and IL-2 receptor alpha chain (CD25) levels in the plasma of patients with mastocytosis: relationships to disease severity and bone marrow pathology. 1094 67

Systemic mastocytosis has one unifying feature: an unexplained and pathologic increase in mast cells in specific tissues. This observation, along with clinical disease heterogeneity has long suggested that mastocytosis is a disease of complex etiology. At the same time, the last decade has witnessed significant progress in identifying the critical elements that regulate mast cell growth and development. Human mast cells are now known to arise from CD34(+) progenitors, particularly under the influence of stem cell factor (SCF). This information in turn led to the critical observation that a substantial number of patients with mastocytosis exhibit activating mutations in c-kit, the receptor for SCF. And while this observation may well be key in understanding mastocytosis, this mutation alone does not explain all heterogeneity. It now appears that other influences such as genetic polymorphisms within the host may influence the course of disease in those with KIT mutations; and that the search for additional molecular events capable of creating disease diversity must continue.
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PMID:Mastocytosis: molecular mechanisms and clinical disease heterogeneity. 1137 83

Several emerging treatment concepts for myeloid neoplasms are based on novel drugs targeting cell surface antigens, signalling pathways, or critical effector molecules. Systemic mastocytosis is a haematopoietic neoplasm that behaves as an indolent myeloproliferative disease in most patients, but can also present as aggressive disease or even as an acute leukaemia. In patients with aggressive disease or mast cell leukaemia, the response to conventional therapy is poor in most cases, and the prognosis is grave. Therefore, a number of attempts have been made to define novel treatment strategies for these patients. One promising approach may be to identify novel targets and to develop targeted drug therapies. In this article, we support the notion that neoplastic mast cells indeed express a number of potential molecular targets including immunoreactive CD antigens, the microphthalmia transcription factor (MITF), and members of the Bcl-2 family. In addition, the tyrosine kinase receptor KIT and downstream signalling pathways have been proposed as targets of a specific pharmacological intervention. A particular challenge is the disease-related D816V-mutated variant of KIT, which is resistant against diverse tyrosine kinase inhibitors including STI571, but may be sensitive to more recently developed targeted compounds. The therapeutic potential of target-specific approaches in malignant mast cell disorders should be evaluated in forthcoming clinical trials in the near future.
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PMID:On the way to targeted therapy of mast cell neoplasms: identification of molecular targets in neoplastic mast cells and evaluation of arising treatment concepts. 1529 5

Mast cell disorders are defined by an abnormal accumulation of tissue mast cells (MCs) in one or more organ systems. Symptoms in mastocytosis result from MC-derived mediators and, less frequently, from destructive infiltration of MCs. Cutaneous mastocytosis (CM) is a benign disease of the skin and may regress spontaneously. Systemic mastocytosis (SM) is a persistent disease in which a somatic c-kit mutation at codon 816 is usually detectable in MCs and their progenitors. The clinical course in these patients is variable ranging from asymptomatic for years to highly aggressive and rapidly devastating. The WHO discriminates five categories of SM: indolent SM (ISM), aggressive SM (ASM), SM with associated clonal hematological non-MC-lineage disease (AHNMD), and mast cell leukemia (MCL). The c-kit mutation D816V is quite common and may be found in all SM-categories. In SM-AHNMD, additional genetic abnormalities have been reported, whereas no additional defects are yet known for ASM or MCL. Patients with ISM and CM are treated with "mediator-targeting" drugs, whereas patients with ASM or MCL are candidates for cytoreductive therapy. The use of "Kit-targeting" tyrosine kinase inhibitors such as STI571 (Imatinib, Gleevec), has also been suggested. However, the D816V mutation of c-kit is associated with relative resistance against STI571. Therefore, these patients require alternative targeted drugs or new drug-combinations. In patients with SM-AHNMD, separate treatment plans for the SM-component and the AHNMD should be established. Examples include the use of STI571 in patients with SM plus hypereosinophilic syndrome (SM-HES) and the FIPL1/PDGFRA fusion gene target, or chemotherapy for eradication of AML in patients with SM-AML.
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PMID:Mastocytosis: pathology, genetics, and current options for therapy. 1562 79

Systemic mastocytosis is characterized by abnormal mast cell proliferation in different organs. The 2001 consensus classification distinguishes in separate categories indolent systemic mastocytosis, systemic mastocytosis with concomitant blood disease, aggressive systemic mastocytosis and mast cell leukemia. Clinical manifestations are caused by tissue infiltration by proliferating mastocytes and by release of mediators. The principal organs affected are the skin, bones, digestive tract, liver, spleen and lymph nodes. Diagnosis of mastocytosis is based on appropriate stains (Giemsa, toluidine blue) and immunophenotype features (tryptase, CD117, also known as c-KIT and stem cell factor receptor). Serum tryptase levels reflect the total mast cell burden. Treatment must prevent release of mast cell mediators (histamine antagonists, cromolyn sodium, corticosteroids, or leukotriene-receptor inhibitors), limit bone involvement (bisphosphonates) and reduce the number of circulating mast cells (interferon, cladribine, or tyrosine kinase inhibitors). Enhanced understanding of the pathogenic mechanisms (mutation of c-kit and platelet-derived growth factor receptor alpha has led to the development of targeted treatments, including new inhibitors of tyrosine kinase and of nuclear factor Kappa B.
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PMID:[Systemic mastocytosis]. 1598 48

Systemic mast cell disorders in most instances appear to be clonal disorders of the mast cell and its progenitor. Symptoms result from a pathological release of mast cell mediators and a destructive mast cell infiltration. Cutaneous mastocytosis is most frequently seen in children and may regress. Systemic mastocytosis (SM) is a persistent disease. A somatic c-kit mutation at codon 816 is often detectable in haematopoietic cells. The clinical course of mastocytosis is variable, ranging from indolent to aggressive. Five categories of disease are recognized: Indolent SM, aggressive SM, SM with associated clonal haematological non-mast cell-lineage disease (AHNMD) and mast cell leukaemia (MCL). In SM-AHNMD, additional genetic abnormalities have been reported. Patients with cutaneous or indolent systemic disease are treated symptomatically. Patients with aggressive disease are candidates for cytoreductive therapy. The use of 'Kit-targeting' tyrosine kinase inhibitors are best selected following a mutational analysis of c-kit. For instance, the D816V mutation appears to be associated with relative resistance against imatinib. However, imatinib has been used with success in patients with SM-hypereosinophilic syndrome (HES) and the FIPL1/PDGFRA fusion gene and in a patient with mastocytosis with a mutation outside of codon 816. The value of bone marrow transplantation remains under investigation.
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PMID:Mastocytosis. 1660 39

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

Systemic mast cell disease is characterized by dysregulated mast cell growth and survival, with infiltration into multiple organs and release of systemic mediators. Much has been learned about mast cell biology over the past 20 years, and it has become apparent that activating mutations in the c-KIT receptor tyrosine kinase underlie the aberrant cell signaling and mast cell growth in a majority of patients. Despite this knowledge, targeted therapy with imatinib has been largely unsuccessful due to resistance of the common c-KIT D816V (Asp-->Val) mutation. Novel strategies designed to inhibit the growth of mast cells containing the c-KIT D816V mutations have shown success in vitro and may provide effective targeted therapy for this treatment-refractory disease.
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PMID:Systemic mastocytosis: current classification and novel therapeutic options. 1709 33

MCL-1 is a Bcl-2 family member that has been described as antiapoptotic in various myeloid neoplasms. Therefore, MCL-1 has been suggested as a potential new therapeutic target. Systemic mastocytosis (SM) is a myeloid neoplasm involving mast cells (MCs) and their progenitors. In the present study, we examined the expression and functional role of MCL-1 in neoplastic MCs and sought to determine whether MCL-1 could serve as a target in SM. As assessed by RT-PCR and immunohistochemical examination, primary neoplastic MCs expressed MCL-1 mRNA and the MCL-1 protein in all SM patients examined. Moreover, MCL-1 was detectable in both subclones of the MC line HMC-1--HMC-1.1 cells, which lack the SM-related KIT mutation D816V, and HMC-1.2 cells, which carry KIT D816V. Exposure of HMC-1.1 cells or HMC-1.2 cells to MCL-1-specific antisense oligonucleotides (ASOs) or MCL-1-specific siRNA resulted in reduced survival and increased apoptosis compared with untreated cells. Moreover, MCL-1 ASOs were found to cooperate with various tyrosine kinase inhibitors in producing growth inhibition in neoplastic MCs, with synergistic effects observed with PKC412, AMN107, and imatinib in HMC-1.1 cells and with PKC412 in HMC-1.2 cells. Together, these data show that MCL-1 is a novel survival factor and an attractive target in neoplastic MCs.
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PMID:Identification of MCL1 as a novel target in neoplastic mast cells in systemic mastocytosis: inhibition of mast cell survival by MCL1 antisense oligonucleotides and synergism with PKC412. 1711 Apr 60

Systemic mastocytosis (SM) is a myeloid neoplasm characterized by increased survival and accumulation of neoplastic mast cells (MCs). In most patients, the D816V-mutated variant of KIT is detectable. We report here that heat shock protein 32 (Hsp32), also known as heme oxygenase-1 (HO-1), is a novel KIT-inducible survival factor in neoplastic MCs. As assessed by reverse transcription-polymerase chain reaction (RT-PCR), immunocytochemistry, and Western blotting, the KIT D816V(+) MC line HMC-1.2 as well as highly enriched primary neoplastic MCs were found to express Hsp32 mRNA and the Hsp32 protein. Moreover, KIT D816V and stem cell factor (SCF)-activated wild-type KIT were found to induce Hsp32 promoter activity, expression of Hsp32 mRNA, and expression of the Hsp32 protein in Ba/F3 cells. Correspondingly, the KIT D816V-targeting drug PKC412 decreased the expression of Hsp32 as well as proliferation/survival in neoplastic MCs. The inhibitory effects of PKC412 on the survival of HMC-1.2 cells were counteracted by the HO-1 inductor hemin or lentiviral-transduced HO-1. Moreover, 2 Hsp32-targeting drugs, pegylated zinc protoporphyrin (PEG-ZnPP) and styrene maleic acid copolymer micelle-encapsulated ZnPP (SMA-ZnPP), were found to inhibit proliferation and to induce apoptosis in neoplastic MCs. Furthermore, both drugs were found to cooperate with PKC412 in producing growth inhibition. Together, these data show that Hsp32 is an important survival factor and interesting new therapeutic target in neoplastic MCs.
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PMID:Identification of heat shock protein 32 (Hsp32) as a novel survival factor and therapeutic target in neoplastic mast cells. 1742 Feb 86


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