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)

Hypereosinophilic syndrome (HES) is a heterogeneous group of disorders characterized by unexplained persistent primary eosinophilia causing end-organ damage. We conducted a prospective cohort study of patients fulfilling the diagnostic criteria for HES. Of 20 patients considered eligible for the study, 2 were found to have clonal myeloid disorders, limiting the diagnosis of "true" HES to 18 patients. No patient carried the FIP1L1-PDGFRA fusion gene or other imatinib-responsive translocations. A clonal interleukin-5-producing T-cell population was not detected in any patient. Common manifestations at presentation were pulmonary, cutaneous, and neurologic involvement; serositis; and gastrointestinal involvement. Only 3 patients developed cardiac involvement. Fifteen of the HES patients were administered first-line combined treatment with steroids and hydroxyurea. Nine patients achieved complete response, while 6 attained only partial response. Imatinib was administered to 3 HES patients who had been pretreated with steroids, resulting in complete hematologic and clinical response in 2 patients and no response at all in 1. Further treatment of the latter patient with steroids and hydroxyurea also proved ineffective. We conclude that the therapeutic approach should be individualized according to molecular findings. We consider the coadministration of corticosteroids and hydroxyurea to be an effective combination for the treatment of FIP1L1-PDGFRA-negative HES.
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PMID:Management of hypereosinophilic syndrome: a prospective study in the era of molecular genetics. 1800 79

Hypereosinophilic syndromes (HES) are a heterogeneous group of disorders characterized by marked peripheral blood and tissue eosinophilia resulting in organ damage. Recent advances in molecular biology have led to the identification of a FIP1L1-PDGFRA fusion gene as a recurrent abnormality in some patients with HES. This fusion gene results from a cryptic 4q12 interstitial deletion involving an 800 kb region. Recent reports indicate that this subtype of HES is imatinib responsive with rapid and complete haematological remissions. Here we report two patients successfully treated with imatinib.
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PMID:[Efficacy of imatinib in FIP1L1-PDGFRA positive hypereosinophilic syndrome]. 1803 6

Reversal of eosinophilic inflammation has been an elusive therapeutic goal in the management of asthma pathogenesis. In this regard, GM-CSF is a primary candidate cytokine regulating eosinophil activation and survival in the lung; however, its molecular mechanism of propagation and maintenance of stimulated eosinophil activation is not well understood. In this study, we elucidate those late interactions occurring between the GM-CSF receptor and activated eosinophil signaling molecules. Using coimmunoprecipitation with GM-CSF-stimulated eosinophils, we have identified that the GM-CSF receptor beta-chain (GMRbeta) interacted with ICAM-1 and Shp2 phosphatase, as well as Slp76 and ADAP adaptor proteins. Separate experiments using affinity binding with a tyrosine-phosphorylated peptide containing an ITIM (ICAM-1 residues 480-488) showed binding to Shp2 phosphatase and GMRbeta. However, the interaction of GMRbeta with the phosphorylated ICAM-1-derived peptide was observed only with stimulated eosinophil lysates, suggesting that the interaction of GMRbeta with ICAM-1 required phosphorylated Shp2 and/or phosphorylated GMRbeta. Importantly, we found that inhibition of ICAM-1 in activated eosinophils blocked GM-CSF-induced expression of c-fos, c-myc, IL-8, and TNF-alpha. Moreover, inhibition of ICAM-1 expression with either antisense oligonucleotide or an ICAM-1-blocking Ab effectively inhibited ERK activation and eosinophil survival. We concluded that the interaction between ICAM-1 and the GM-CSF receptor was essential for GM-CSF-induced eosinophil activation and survival. Taken together, these results provide novel mechanistic insights defining the interaction between ICAM-1 and the GM-CSF receptor and highlight the importance of targeting ICAM-1 and GM-CSF/IL-5/IL-3 receptor systems as a therapeutic strategy to counter eosinophilia in asthma.
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PMID:Cross-talk between ICAM-1 and granulocyte-macrophage colony-stimulating factor receptor signaling modulates eosinophil survival and activation. 1832 30

Rearrangements of the genes encoding the fibroblast growth factor receptor 1 (FGFR1) and platelet-derived growth factor receptors (PDGFR) alpha or beta receptor tyrosine kinases are found in a rare but important subset of patients with atypical myeloproliferative disorders that are usually but not always associated with eosinophilia. Chromosomal translocations or other rearrangements at 8p11-12, 4q12 or 5q31-33 give rise to diverse fusion genes encoding chimaeric proteins with constitutive transforming activity. There is considerable molecular heterogeneity with 8 partner genes currently known for FGFR1, 6 for PDGFRA and 17 for PDGFRB. The vast majority of patients with PDGFRA or PDGFRB fusions achieve rapid and durable complete haematological and molecular responses to sustained imatinib therapy. A key ongoing challenge is to define the molecular pathogenesis of the great majority of atypical myeloproliferative disorders for whom the causative lesion remains unknown, since very few of these cases gain any benefit from imatinib or other second-generation inhibitors.
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PMID:Fibroblast growth factor receptor and platelet-derived growth factor receptor abnormalities in eosinophilic myeloproliferative disorders. 1856 37

We report a 61-year-old man with chronic eosinophilic leukemia (CEL). The patient was referred to our hospital because of pyrexia and eosinophilia. He was diagnosed with CEL based on an increase in blasts and eosinophils in his peripheral blood and bone marrow, and clonal complex karyotypic abnormalities including trisomy 8. The FIP1L1-PDGFRA fusion transcript was not detected by RT-PCR analysis. Although he had no obvious organ damage at diagnosis, pulmonary infiltrates in the right lung and multiple skin nodules over his whole body appeared over 4 months and progressed rapidly, accompanied by a marked increase in blasts in his peripheral blood. CEL with trisomy 8 has been reported to be associated with transformation into acute leukemia and granulocytic sarcoma in the literature. It is notable that the present case was associated with complex karyotypic abnormalities and the exceptionally marked disease progression. Further analyses of clinical data as well as molecular genetic findings of CEL without known karyotypic abnormalities leading to constitutive activation of tyrosine-kinase genes are needed to gain insight into the pathogenesis of CEL and to develop a new disease classification and treatment strategies.
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PMID:[Chronic eosinophilic leukemia with complex karyotypic abnormalities including trisomy 8]. 1870 84

The year 2008 marks the fifth anniversary since the publication which identified the FIP1L1-PDGFRA fusion gene in patients with idiopathic hypereosinophilia. With the benefit of time, a more comprehensive picture has emerged regarding several characteristics of the fusion, including its incidence, biological features and the clinical profile of patients who carry the molecular rearrangement. A few prospective trials have now better defined the natural history of imatinib-treated FIP1L1-PDGFRA-positive patients, from which some basic conclusions can be drawn: the prognosis is outstanding, acquired resistance is exceedingly rare, but ongoing imatinib treatment is likely required to prevent relapse. The emergence of genetically assigned eosinophilias has led the World Health Organization in 2008 to adopt a semi-molecular classification scheme, with one subcategory named 'myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1.' Molecular rearrangements involving other partner genes, such as ETV6 and JAK2, have also been associated with eosinophilic disorders, and will likely be assimilated into such classifications over time. Despite the molecularly defined eosinophilias comprising a small proportion of cases compared to the aggregate of other subtypes of hypereosinophilia, their recognition is critical because of the availability of highly effective molecularly targeted therapy.
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PMID:Five years since the discovery of FIP1L1-PDGFRA: what we have learned about the fusion and other molecularly defined eosinophilias. 1884 83

The FIP1L1-PDGFRA fusion gene is a recurrent molecular abnormality in patients with eosinophilia-associated myeloproliferative neoplasms. We characterized FIP1L1-PDGFRA junction sequences from 113 patients at the mRNA (n=113) and genomic DNA (n=85) levels. Transcript types could be assigned in 109 patients as type A (n=50, 46%) or B (n=47, 43%), which were created by cryptic acceptor splice sites in different introns of FIP1L1 (type A) or within PDGFRA exon 12 (type B). We also characterized a new transcript type C (n=12, 11%) in which both genomic breakpoints fell within coding sequences creating a hybrid exon without use of a cryptic acceptor splice site. The location of genomic breakpoints within PDGFRA and the availability of AG splice sites determine the transcript type and restrict the FIP1L1 exons used for the creation of the fusion. Stretches of overlapping sequences were identified at the genomic junction site, suggesting that the FIP1L1-PDGFRA fusion is created by illegitimate non-homologous end-joining. Statistical analyses provided evidence for clustering of breakpoints within FIP1L1 that may be related to DNA- or chromatin-related structural features. The variability in the anatomy of the FIP1L1-PDGFRA fusion has important implications for strategies to detect the fusion at diagnosis or for monitoring response to treatment.
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PMID:The molecular anatomy of the FIP1L1-PDGFRA fusion gene. 1898 51

Hypereosinophilic syndromes (HES) constitute a rare and heterogeneous group of disorders, defined as persistent and marked blood eosinophilia associated with evidence of eosinophil-induced organ damage. Cardiac dysfunction is the most frequent result of end-organ damage and is the major cause of morbidity and mortality among patients with HES. Despite patients with FIP1-like-1-platelet-derived growth factor alpha (FIP1L1-PDGFRA) associated HES (myeloid neoplasms associated with PDGFRA rearrangement) have been shown to respond to low-dose imatinib with a complete and durable hematological and cytogenetic remission, influences of imatinib on clinical manifestations related to hypereosinophilia heart involvement are variable. Here we describe the case of a young male patient with severe heart involvement who had a prompt, clinical and hematological complete remission following administration of imatinib. However, as endomyocardial fibrosis and related loss of function are deteriorated after initiation of imatinib therapy, valvular replacement and tricuspid annuloplasty had to perform to restore his heart function. Our finding concurs with recent reports that severe heart involvement was irreversible with imatinib treatment.
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PMID:Successful treatment of myeloid neoplasms associated with PDGFRA rearrangement with imatinib mesylate. 1909 55

The PDGRFA locus has become a gene of interest based on mutational activation in various myeloid neoplasms and the availability of targeted therapies (i.e., imatinib mesylate) to its overexpression. We studied a new FISH method to detect CHIC2 deletion, FIP1L1/PDGFRA fusion and PDGFRA translocation in patients with myeloid neoplasms associated with eosinophilia. A total of 46 specimens were studied, including 15 from patients with a CHIC2 abnormality and six patients with an abnormality involving PDGFRA. Our results revealed this new FISH assay accurately detects these abnormalities and will be a useful clinical test for patients with myeloid neoplasms and eosinophilia.
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PMID:Validation of a new three-color fluorescence in situ hybridization (FISH) method to detect CHIC2 deletion, FIP1L1/PDGFRA fusion and PDGFRA translocations. 1911 97

Therapeutically validated oncoproteins in myeloproliferative neoplasms (MPN) include BCR-ABL1 and rearranged PDGFR proteins. The latter are products of intra- (e.g. FIP1L1-PDGFRA) or inter-chromosomal (e.g. ETV6-PDGFRB) gene fusions. BCR-ABL1 is associated with chronic myelogenous leukaemia (CML) and mutant PDGFR with an MPN phenotype characterized by eosinophilia and in addition, in case of FIP1L1-PDGFRA, bone marrow mastocytosis. These genotype-phenotype associations have been effectively exploited in the development of highly accurate diagnostic assays and molecular targeted therapy. It is hoped that the same will happen in other MPN with specific genetic alterations: polycythemia vera (JAK2 V617F and other JAK2 mutations), essential thrombocythemia (JAK2V617F and MPL515 mutations), primary myelofibrosis (JAK2 V617F and MPL515 mutations), systemic mastocytosis (KITD816V and other KIT mutations) and stem cell leukaemia/lymphoma (ZNF198-FGFR1 and other FGFR1 fusion genes). The current review discusses the above listed mutant molecules in the context of their value as drug targets.
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PMID:Molecular drug targets in myeloproliferative neoplasms: mutant ABL1, JAK2, MPL, KIT, PDGFRA, PDGFRB and FGFR1. 1917 93


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