Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Dysregulation of receptor tyrosine kinase (RTK) activity has been implicated in the progression of a variety of human leukemias. Most notably, mutations and chromosomal translocations affecting regulation of tyrosine kinase activity in the Kit receptor, the Flt3 receptor, and the PDGFbeta/FGF1 receptors have been demonstrated in mast cell leukemia, acute myeloid leukemia (AML), and chronic myelogenous leukemias (CML), respectively. In addition, critical but non-overlapping roles for the Ron and Kit receptor tyrosine kinases in the progression of animal models of erythroleukemia have been demonstrated [Persons, D., Paulson, R., Loyd, M., Herley, M., Bodner, S., Bernstein, A., Correll, P. and Ney, P., 1999. Fv2 encodes a truncated form of the Stk receptor tyrosine kinase. Nat. Gen. 23, 159-165.; Subramanian, A., Teal, H.E., Correll, P.H. and Paulson, R.F., 2005. Resistance to friend virus-induced erythroleukemia in W/Wv mice is caused by a spleen-specific defect which results in a severe reduction in target cells and a lack of Sf-Stk expression. J. Virol. 79 (23), 14586-14594.]. The various classes of RTKs implicated in the progression of leukemia have been recently reviewed [Reilly, J., 2003. Receptor tyrosine kinases in normal and malignant haematopoiesis. Blood Rev. 17 (4), 241-248.]. Here, we will discuss the mechanism by which alterations in these receptors result in transformation of hematopoietic cells, in the context of what is known about the molecular regulation of RTK activity, with a focus on our recent studies of the Ron receptor tyrosine kinase.
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PMID:Molecular regulation of receptor tyrosine kinases in hematopoietic malignancies. 1652 73

Aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL) are rare but devastating diseases, for which no effective specific therapy is currently available. Most patients harbor the D816V mutant of KIT (KIT(D816V)), a constitutively active tyrosine kinase that is essential for pathogenesis, raising hopes that specific inhibition of KIT(D816V) may be therapeutically efficacious. To facilitate testing of new inhibitors in an animal model with similarity to human ASM/MCL, we developed a murine model that is based on retro-orbital injection of P815 cells, a murine mastocytoma line expressing the homologous D814Y mutant of KIT, into syngeneic DBA/2 mice. We found that the systemic disease induced by this approach is highly reproducible and resembles human ASM/MCL. Malignant mast cells were consistently detected in the peripheral blood by morphology and fluorescence-activated cell sorting after a stable latency whose length could be modulated by inoculum size. This easy and inexpensive tumor model should be useful for testing potential drugs with activity against KIT(D816V).
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PMID:Establishment of a murine model of aggressive systemic mastocytosis/mast cell leukemia. 1654 62

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

Serum (or plasma) levels of total and mature tryptase measurements are recommended in the diagnostic evaluation of systemic anaphylaxis and systemic mastocytosis, but their interpretation must be considered in the context of a complete workup of each patient. Total tryptase levels generally reflect the increased burden of mast cells in patients with all forms of systemic mastocytosis (indolent systemic mastocytosis, smoldering systemic mastocytosis, systemic mastocytosis associated with a hematologic clonal non-mast cell disorder, aggressive systemic mastocytosis, and mast cell leukemia) and the decreased burden of mast cells associated with cytoreductive therapies in these disorders. Causes of an elevated total tryptase level other than systemic mastocytosis must be considered, however, and include systemic anaphylaxis, acute myelocytic leukemia, various myelodysplastic syndromes, hypereosinophilic syndrome associated with the FLP1L1-PDGFRA mutation, end-stage renal failure, and treatment of onchocerciasis. Mature (beta) tryptase levels generally reflect the magnitude of mast cell activation and are elevated during most cases of systemic anaphylaxis, particularly with parenteral exposure to the inciting agent.
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PMID:Diagnostic value of tryptase in anaphylaxis and mastocytosis. 1693 Dec 88

Vascular endothelial growth factor (VEGF) is produced in neoplastic cells in various myeloid neoplasms and may act as an autocrine growth-regulator. We have examined the expression of five VEGF receptors (VEGR1/Flt-1, VEGFR2/KDR, Flt-4, neuropilin-1 = NRP-1, NRP-2) in leukemic cells obtained from patients with acute myeloid leukemia (n = 28), chronic myeloid leukemia (n = 14), chronic eosinophilic leukemia (n = 3), chronic myelomonocytic leukemia (n = 9), or mast cell leukemia/systemic mastocytosis (n = 3) as well as in respective cell lines. Expression of VEGFR mRNA was analyzed by RT-PCR, and expression of VEGFR protein by immunocytochemistry. In most patients, leukemic cells expressed NRP-1 mRNA and NRP-2 mRNA independent of the type of disease. By contrast, transcripts for Flt-1, KDR, and Flt-4 were expressed variably without a clear correlation to the type of leukemia. Expression of VEGF receptors was also demonstrable at the protein level in all cases tested. In conclusion, neoplastic cells in myeloid leukemias frequently express VEGFR including NRP-1 and NRP-2.
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PMID:Myeloid leukemias express a broad spectrum of VEGF receptors including neuropilin-1 (NRP-1) and NRP-2. 1791 67

Gain-of-function mutations in the proto-oncogene c-kit that induce constitutive kinase activity of its product, KIT protein, are characteristic of human mast cell disease and are believed to play a central role in mast cell leukemia oncogenesis, proliferation and survival. Nuclear overexpression of the Wnt effector beta-catenin and deregulated beta-catenin nuclear signaling can promote malignant transformation in solid tumors and hematologic malignancies. However, a role for beta-catenin in mast cell leukemia has not been described. Nuclear accumulation of beta-catenin is upregulated by its tyrosine phosphorylation, a process that can be exacerbated by deregulated expression of oncogenic tyrosine kinases. Here, we investigated the relationship between activated KIT and beta-catenin signaling in mast cell leukemia. Beta-catenin was tyrosine-phosphorylated in cells with KIT activated by either gain-of-function mutation or incubation with the KIT ligand stem cell factor. Beta-catenin tyrosine phosphorylation depended on KIT activity but not on PI3K-AKT activation. Tyrosine phosphorylation of beta-catenin was associated with its nuclear localization and enhanced transcription of target genes c-myc and cyclin D1. Endogenous KIT and beta-catenin were found to associate in mast cell leukemia cells, and in vitro kinase assay demonstrated that active KIT phosphorylates tyrosine residues of beta-catenin directly. Aberrant beta-catenin-driven transcription caused by deregulated KIT may represent a significant new target for treatment of mast cell leukemia.
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PMID:KIT regulates tyrosine phosphorylation and nuclear localization of beta-catenin in mast cell leukemia. 1794 10

KIT mutations have been identified in several malignancies, including acute myeloid leukemia (AML) and systemic mastocytosis (SM). Mast cell leukemia (MCL) is the most aggressive mast cell neoplasm, but has not been well studied due to its rarity. We identified novel KIT transcripts in two patients with MCL and two patients with SM with an associated hematological disorder, but not from two patients with SM. Similar novel KIT transcripts were also observed in normal CD34+ cells from bone marrow and umbilical cord blood, suggesting that altered KIT isoforms may be specific to the blast stage of hematopoietic precursors. The novel KIT proteins lack several domains including the ATP binding site, and one was inactive in a functional test for autophosphorylation. Our discovery of novel KIT transcripts underscores the importance of analysing entire protein encoding regions when studying genes of interest.
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PMID:The identification and characterisation of novel KIT transcripts in aggressive mast cell malignancies and normal CD34+ cells. 1876 58

The ectoenzyme E-NPP3 (CD203c) has recently been identified as a novel activation-linked cell surface antigen on basophils. In the present study, we examined expression of CD203c on normal mast cells (MC)and bone marrow (bm) MC derived from 85 patients with systemic mastocytosis (SM), including cases with indolent SM (ISM, n=72), SM with associated clonal hematologic non-MC-lineage disease (SM-AHNMD, n=6), aggressive SM (ASM, n=3), and mast cell leukemia (MCL, n=4). Surface expression of CD203c was analyzed by multicolor flow cytometry. In patients with SM, bm MC expressed significantly higher amounts of CD203c compared to normal bm MC (median MFI in controls: 260 versus median MFI in SM: 516, p<0.05). Slightly lower amounts of CD203c were detected on MC in SM-AHNMD and ASM compared to ISM. To demonstrate CD203c expression in MC at the mRNA level, neoplastic MC were highly enriched by cell sorting, and were found to express CD203c mRNA in RT-PCR analysis. Cross-linking of the IgE receptor on MC resulted in a substantial upregulation of CD203c, whereas the KIT-ligand stem cell factor (SCF) showed no significant effects. In conclusion, CD203c is a novel activation-linked surface antigen on MC that is upregulated in response to IgE receptor cross-linking and is overexpressed on neoplastic MC in patients with SM.
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PMID:CD203c is overexpressed on neoplastic mast cells in systemic mastocytosis and is upregulated upon IgE receptor cross-linking. 1914 65

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

Recent data suggest that the signal transducer and activator of transcription (STAT)5 contributes to differentiation and growth of mast cells. It has also been described that constitutively phosphorylated STAT5 (pSTAT5) plays a pro-oncogenic role in various myeloid neoplasms. We examined the expression of pSTAT5 in neoplastic mast cells in systemic mastocytosis and asked whether the disease-related oncoprotein KIT D816V is involved in STAT5 activation. As assessed by immunohistochemistry using the anti-pSTAT5 antibody AX1, neoplastic mast cells were found to display pSTAT5 in all SM patients examined (n = 40). Expression of pSTAT5 was also demonstrable in the KIT D816V-positive mast cell leukemia cell line HMC-1. Using various staining-protocols, pSTAT5 was found to be located in both the cytoplasmic and nuclear compartment of mast cells. To define the functional role of KIT D816V in STAT5-activation, Ba/F3 cells with doxycycline-inducible expression of KIT D816V were used. In these cells, induction of KIT D816V resulted in an increased expression of pSTAT5 without substantial increase in total STAT5. Moreover, the KIT D816V-targeting kinase-inhibitor PKC412 was found to counteract expression of pSTAT5 in HMC-1 cells as well as doxycycline-induced expression of pSTAT5 in Ba/F3 cells. Finally, a dominant negative STAT5-construct was found to inhibit growth of HMC-1 cells. Together, our data show that neoplastic mast cells express cytoplasmic and nuclear pSTAT5, that KIT D816V promotes STAT5-activation, and that STAT5-activation contributes to growth of neoplastic mast cells.
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PMID:Expression of activated STAT5 in neoplastic mast cells in systemic mastocytosis: subcellular distribution and role of the transforming oncoprotein KIT D816V. 1989 34


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