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)

We recently identified the chimeric kinase FIP1L1-platelet-derived growth factor receptor alpha (PDGFRalpha) as a cause of the hypereosinophilic syndrome and of chronic eosinophilic leukemia. To investigate the role of FIP1L1-PDGFRA in the pathogenesis of acute leukemia, we screened 87 leukemia cell lines for the presence of FIP1L1-PDGFRA. One cell line, EOL-1, expressed the FIP1L1-PDGFRA fusion. Three structurally divergent kinase inhibitors--imatinib (STI-571), PKC412, and SU5614--inhibited the growth of EOL-1 cells. These results indicate that the fusion of FIP1L1 to PDGFRA occurs rarely in leukemia cell lines, but they identify EOL-1 as an in vitro model for the study of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia and for the analysis of small molecule inhibitors of FIP1L1-PDGFRalpha.
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PMID:The EOL-1 cell line as an in vitro model for the study of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia. 1463 Jul 92

Detection of the FIP1L1-PDGFRA fusion gene or the corresponding cryptic 4q12 deletion supports the diagnosis of chronic eosinophilic leukemia (CEL) in patients with chronic hypereosinophilia. We retrospectively characterized 17 patients fulfilling WHO criteria for idiopathic hypereosinophilic syndrome (IHES) or CEL, using nested RT-PCR and interphase fluorescence in situ hybridization (FISH). Eight had FIP1L1-PDGFRA (+) CEL, three had FIP1L1-PDGFRA (-) CEL and six had IHES. FIP1L1-PDGFRA (+) CEL responded poorly to steroids, hydroxyurea or interferon-alpha, and had a high probability of eosinophilic endomyocarditis (n=4) and disease-related death (n=4). In FIP1L1-PDGFRA (+) CEL, palpable splenomegaly was present in 5/8 cases, serum vitamin B(12) was always markedly increased, and marrow biopsies revealed a distinctively myeloproliferative aspect. Imatinib induced rapid complete hematological responses in 4/4 treated FIP1L1-PDGFRA (+) cases, including one female, and complete molecular remission in 2/3 evaluable cases. In the female patient, 1 log reduction of FIP1L1-PDGFRA copy number was reached as by real-time quantitative PCR (RQ-PCR). Thus, correlating IHES/CEL genotype with phenotype, FIP1L1-PDGFRA (+) CEL emerges as a homogeneous clinicobiological entity, where imatinib can induce molecular remission. While RT-PCR and interphase FISH are equally valid diagnostic tools, the role of marrow biopsy in diagnosis and of RQ-PCR in disease and therapy monitoring needs further evaluation.
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PMID:Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias. 1497 4

Primary (nonreactive) eosinophilia is operationally classified as either a "clonal" or an "idiopathic" process. Clonal eosinophilia stipulates the presence of cytogenetic, molecular, or bone marrow histologic evidence of acute leukemia or a chronic myeloid disorder. Idiopathic eosinophilia is a diagnosis of exclusion that is made after ruling out both "secondary" (reactive) and clonal eosinophilia. Hypereosinophilic syndrome is a subclass of idiopathic eosinophilia that requires the documentation of both sustained eosinophilia (> or = 1500/microL for at least 6 months) and target-organ damage. A series of novel observations in the last 5 years have warranted a refined approach to the diagnosis as well as the treatment of clonal eosinophilic disorders, including systemic mastocytosis. At the center of these new developments are mutations involving the platelet-derived growth factor receptor genes (PDGFRA and PDGFRB), which have been pathogenetically linked to clonal eosinophilia, and their presence predicts complete as well as durable treatment responses to imatinib mesylate. The bone marrow histologic phenotype of these imatinib-sensitive eosinophilic disorders includes systemic mastocytosis, chronic eosinophilic leukemia, chronic myelomonocytic leukemia, and atypical chronic myeloproliferative disorder.
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PMID:Imatinib therapy in clonal eosinophilic disorders, including systemic mastocytosis. 1523 93

Chronic eosinophilic leukemia is a neoplastic condition with persistent eosinophilia as the major hematological abnormality and with the eosinophils being part of the neoplastic clone. Some cases can be recognized by traditional hematological criteria, but many can be recognized only when a clonal cytogenetic or molecular genetic abnormality is demonstrated. A range of cytogenetic and molecular genetic abnormalities has been recognized, including both those seen in other myeloid malignancies (such as trisomy 8, monosomy 7, and 20q-) and those that are particularly linked to eosinophil differentiation (such as rearrangements of PDGFRB, FGFR1, and PDGFRA, the latter with formation of a FIP1L1-PDGFRA fusion gene). The discovery of the FIP1L1-PDGFRA fusion gene has led to the recognition that many patients who would previously have been regarded as having idiopathic hypereosinophilia actually have chronic eosinophilic leukemia. The same fusion gene has also been found in patients with hypereosinophilia and atypical bone marrow mast cells but whether this syndrome should be regarded as a variant of eosinophilic leukemia or as a variant of systemic mastocytosis remains to be established.
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PMID:Relationship between idiopathic hypereosinophilic syndrome, eosinophilic leukemia, and systemic mastocytosis. 1530 12

Endomyocardial fibrosis (Loeffler's endocarditis) is the main cause of poor outcome in Hyper Eosinophilic Syndrome (HES) and Eosinophilic Leukemia (EL). Reversion of the cardiac damage has been seldom reported, and thrombi can superimpose on infiltrated walls, originating oembolic complications. The tyrosine kynase inhibitor imatinib has been recently employed in patients affected by HES or EL, with impressive results. We have treated with imatinib a young patient affected by Loeffler's endocarditis during EL. Loeffler's endocarditis was studied by transthoracic Doppler echocardiography with and without the contrast agent SonoVue. Cytogenetics, FISH and molecular analysis showed the presence of the FIP1L1/PDGFRA fusion gene, recently detected in a majority of HES patients. Standard echocardiography revealed a large infiltration of the apical region, with apparently pedunculate corpora floating in the LV chamber; after SonoVue injection, a thick endo-myocardial infiltration involving papillary muscles and tendinous chords appeared, which simulated mobile thrombi at standard echography. Treatment with low dose imatinib caused rapid regression of both eosinophilic proliferation and endomyocardiopathy. The fusion gene FIP1L1-PDGFRA was found significantly decreased after a few months of treatment. Using a contrast echocardiographic approach, we demonstrated the non-thrombotic origin of the "in plus" image in our patient and its rapid resolution following imatinib treatment. Imatinib is an excellent candidate for first line treatment of Loeffler's endocarditis, especially when the FIP1L1/PDGFA fusion gene is detected.
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PMID:Rapid reversion of Loeffler's endocarditis by imatinib in early stage clonal hypereosinophilic syndrome. 1562 68

Mast cell disease (MCD) is characterized by the abnormal growth and accumulation of neoplastic mast cells (MC) in one or more organs. The diagnosis of systemic MCD is most commonly established by a thorough histological and immunohistochemical examination of a bone marrow (BM) trephine specimen. In cases with pathognomonic perivascular and -trabecular aggregates of morphologically atypical MC and significant BM involvement, the diagnosis may be relatively straightforward. In contrast, when a sparse, loose pattern of MC infiltration predominates, or when MCs are obscured by an associated non-MC hematological neoplasm, a high index of suspicion and use of adjunctive tests, including special stains, such as tryptase and CD25, may be necessary to reach a diagnosis. The updated classification for MCD clarifies the clinical and pathological criteria for categorizing patients into relatively discrete subgroups. Some cases, however, such those with Fip1-like-1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA)(+) clonal eosinophilia associated with elevated serum tryptase levels, with features that overlap MCD and chronic eosinophilic leukemia, may not be easy to categorize on the basis of this classification. There is no standard therapy for MCD and treatment has to be tailored to the needs of the individual patient. MC-cytoreductive therapies, such as interferon-alpha and chemotherapy, are generally reserved for patients with progressive disease and organopathy. A subset of MCD patients with associated eosinophilia who carry the FIP1L1-PDGFRA oncogene will achieve complete clinical, histological, and molecular remissions with imatinib mesylate therapy, in contrast to those with c-kit D816V mutations. The BM pathology, consensus classification, and current therapies for MCD are further discussed in this article.
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PMID:Systemic mastocytosis: bone marrow pathology, classification, and current therapies. 1599 24

The identification of the FIP1L1-PDGFRA fusion gene provides a molecular explanation for the pathogenesis of approximately half of the patients with the hypereosinophilic syndrome (HES). A diagnostic test to identify FIP1L1-PDGFRA positive HES cases (subsequently reclassified as chronic eosinophilic leukemia, CEL) is now available. FIP1L1-PDGFR alpha is a novel therapeutic target of the kinase inhibitor imatinib (Glivec, Novartis), which provides the basis for the treatment of these patients with this drug. FIP1L1-PDGFRA positive CEL patients respond very well to imatinib therapy, some of which are remarkable responses with normalization of the blood counts within 2 weeks after start of the therapy. Imatinib is well tolerated with minimal side effects, and most CEL patients respond to low doses of imatinib (100 mg/day), being important for lowering both the cost of therapy and drug related toxicity. All imatinib treated FIP1L1-PDGFRA positive CEL patients achieve hematological and cytogenetic remission, and the majority of patients also achieve a molecular remission with the fusion gene no longer detectable in blood, even by the most sensitive PCR techniques.
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PMID:FIP1L1-PDGFR alpha, a therapeutic target for the treatment of chronic eosinophilic leukemia. 1608 97

Chronic myeloproliferative diseases (CMPDs) are characterized by the abnormal proliferation and survival of one or more myeloid cell types. The archetype of this class of hematological diseases is chronic myeloid leukemia (CML), characterized by the presence of the Philadelphia (Ph) chromosome, the result of t(9;22)(q34;q11), and the associated BCR-ABL1 oncogene. Some of the Ph-negative myeloproliferative diseases are characterized by other chromosomal translocations involving a variety of tyrosine kinase genes, including ABL1, ABL2, PDGFRA, PDGFRB, FGFR1, and JAK2. The majority of Ph-negative CMPDs, however, such as chronic eosinophilic leukemia, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are not characterized by the presence of recurrent chromosomal abnormalities. Recent studies have identified the FIP1L1-PDGFRA fusion gene, generated due to a small cryptic deletion on chromosome 4q12, and the activating V617F mutation in JAK2 in a significant fraction of Ph-negative CMPDs. These results show that abnormalities in tyrosine kinase genes are central to the molecular pathogenesis of CMPDs. Genome-wide screenings to identify novel tyrosine kinase abnormalities in CMPDs may contribute to further improvement of the diagnosis and the treatment of these diseases.
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PMID:Chronic myeloproliferative disorders: a tyrosine kinase tale. 1634 Oct 34

Idiopathic hypereosinophilic syndrome is a heterogenous group of hematological disorders characterized by eosinophilia (> 1.5 x 10(9)/l) persistent for more than 6 months, exclusion of reactive eosinophilia from other causes, such as parasitic infections or allergy, and evidence of end-organ damage. According to World Health Organization the exclusion includes all neoplastic disorders in which eosinophils are part of the neoplastic clone. Excluded should be also T cell population with aberant phenotype and abnormal cytokine production, recently considert also as "lymphocytic" variants of the HES [42]. HES has to be reclassified as chronic eosinophilic leukemia (CEL) when there is evidence for clonality based on the presence of chromosomal abnormalities or inactivation of X-chromosome in female patients. The successful empiric treatment of patients with tyrosine kinase inhibitor imatinib (Glivec) suggested the presence of an imatinib-sensitive tyrosine kinase inhibitor. The identification of a specific intersticial chromosome deletion del(4)(q12;q12) creating the FIP1L1-PDGFRA fusion gene confirmed this hypothesis. Patients carrying this gene should be reclassified as CEL and detection of this gene is a positive predictor for response to imatinib therapy. Effective doses of imatinib are 100 mg/day. The side effects are minimal. The only exception is an acute left ventricular dysfunction which has been reported in three patients within the first week of treatment with imatinib. Imatinib has been successfully used also in some patients with the constitutively activated thyrosine kinase ETV6-PDGFRbeta [1] and in systemic mast cell disease associated with eosinophilia. Other therapeutical options for HES/CEL have been mentioned. The resistence to imatinib and the possibilities how to overcome it are discussed.
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PMID:[The idiopathic hypereosinophilic syndrome and chronic eosinophilic leukemia]. 1643 Jan 6

Idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia (CEL) are related hematological malignancies characterized by sustained, unexplained hypereosinophilia (>1,500 eosinophils/microL). The term CEL is used when there is evidence that the disease is of clonal origin. We recently identified the FIP1L1-PDGFRA fusion gene in approx 50% of HES/CEL cases. Fusion of FIP1L1 to PDGFRA is the consequence of a deletion on chromosome 4, del(4)(q12q12), with the centromeric breakpoint in FIP1L1 and the telomeric breakpoint in PDGFRA. The breakpoints in FIP1L1 are diverse (introns 7 to 10), but the breakpoints in PDGFRA are always in exon 12 (encoding the juxtamembrane region). Because the chromosomal deletion is only 800 kb in size, it remains undetected with standard cytogenetics. In agreement with this, most patients with HES/CEL present with a normal karyotype. Here we describe three different techniques to detect the presence of the FIP1L1-PDGFRA fusion gene in peripheral blood or bone marrow cells.
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PMID:Detection of the FIP1L1-PDGFRA fusion in idiopathic hypereosinophilic syndrome and chronic eosinophilic leukemia. 1650 85


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