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

---

Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Philadelphia-negative chronic myeloproliferative diseases (CMPD) are very complex and heterogeneous disorders. They are represented by polycythemia vera (PV), chronic idiopathic myelofibrosis (CIMF), essential thrombocythemia (ET), CMPD/unclassifiable (CMPD-U), chronic neutrophilic leukemia (CNL), and chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES) according to the WHO classification. Before, diagnostics were mainly focused on clinical and morphological aspects, but in recent years cytogenetics and fluorescence in situ hybridization (FISH) found entrance in routine schedules as chromosomal abnormalities are relevant for prognosis and classification. Recently, there is rapid progress in the field of molecular characterization: the JAK2V617F mutation which shows a high incidence in PV, CIMF, and ET already plays a central role and will probably soon be included in follow-up procedures. Due to the detection of mutations in exon 12 of the JAK2 gene or mutations in the MPL gene the variety of activating mutations in the CMPD is still increasing. In CEL/HES the detection of the FIP1L1-PDGFRA fusion gene and overexpression of PDGFRA and PDGFRB led to targeted therapy with tyrosine kinase inhibitors. Thus, diagnostics in the CMPD transform toward a multimodal diagnostic concept based on a combination of methods - cyto-/histomorphology, cytogenetics, and individual molecular methods which can be included in a diagnostic algorithm.
...
PMID:[Diagnostic algorithm in chronic myeloproliferative diseases (CMPD)]. 1787 17

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.
...
PMID:Myeloid leukemias express a broad spectrum of VEGF receptors including neuropilin-1 (NRP-1) and NRP-2. 1791 67

Recent years showed significant progress in the molecular characterization of the chronic myeloproliferative disorders (CMPD) which are classified according to the WHO classification of 2001 as polycythemia vera (PV), chronic idiopathic myelofibrosis (CIMF), essential thrombocythemia (ET), CMPD/unclassifiable (CMPD-U), chronic neutrophilic leukemia, and chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome, all to be delineated from BCR/ABL-positive chronic myeloid leukemia (CML). After 2001, the detection of the high frequency of the JAK2V617F mutation in PV, CIMF, and ET, and of the FIP1L1-PDGFRA fusion gene in CEL further added important information in the diagnosis of CMPD. These findings also enhanced the importance of tyrosine kinase mutations in CMPD and paved the way to a more detailed classification and to an improved definition of prognosis using also novel minimal residual disease (MRD) markers. Simultaneously, the broadening of therapeutic strategies in the CMPD, e.g., due to reduced intensity conditioning in allogeneic hematopoietic stem cell transplantation and the introduction of tyrosine kinase inhibitors in CML, in CEL, and in other ABL and PDGRFB rearrangements, increased the demands to diagnostics. Therefore, today, a multimodal diagnostic approach combining cytomorphology, cytogenetics, and individual molecular methods is needed in BCR/ABL-negative CMPD. A stringent diagnostic algorithm for characterization, choice of treatment, and monitoring of MRD will be proposed in this review.
...
PMID:The diagnosis of BCR/ABL-negative chronic myeloproliferative diseases (CMPD): a comprehensive approach based on morphology, cytogenetics, and molecular markers. 1793 25

Imatinib is highly effective for the treatment of chronic eosinophilic leukemia (CEL) caused by the FIP1L1-PDGFRA fusion gene. However, its effectiveness for cardiac involvement of CEL has remained unclear. We describe a 46-year-old man with CEL treated with imatinib. Reverse transcriptase-polymerase chain reaction and sequencing analyses revealed a FIP1L1-PDGFRA fusion transcript with FIP1L1 intron 10 fused to PDGFRA exon 12, and fluorescent in situ hybridization analysis confirmed the interstitial deletion in chromosome 4q12. On admission, the patient had left heart failure accompanied by a large thrombus in the left ventricle. After pretreatment with furosemide and prednisolone, we started imatinib treatment at 100 mg/day. Eosinophilia disappeared within 1 week, and the left ventricular thrombus was resolved within 5 months. At 6 months after starting imatinib, the patient showed grade 4 liver dysfunction. A liver biopsy revealed hepatocyte necrosis with lymphocyte infiltration. Fortunately, the FIP1L1-PDGFRA fusion transcript had become undetectable, and imatinib treatment was stopped. The liver dysfunction resolved within a month. Although the CEL relapsed 6 months later, imatinib could be successfully resumed in combination with 25 mg/day of prednisolone. Thus, imatinib may be very effective for treating the early cardiac involvement of FIP1L1-PDGFRA-positive CEL, but it needs to be used cautiously.
...
PMID:Successful imatinib treatment of cardiac involvement of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia followed by severe hepatotoxicity. 1798 89

Several reports of successful empirical treatment of idiopathic hypereosinophilic syndrome with imatinib led to the recent identification of the FIP1L1-PDGFRA fusion gene rearrangement, which characterizes a distinctive group of chronic eosinophilic leukemias. This fusion gene can be detected in eosinophils, neutrophils, mast cells, T cells, B cells and monocytes in FIP1L1-PDGFRA-positive hypereosinophilic patients suggesting a multilineage involvement. Furthermore, the same FIP1L1-PDGFRA rearrangement was identified in patients with hypereosinophilia and atypical mast cell proliferations, raising the question of a disease with two concomitant lines of differentiation. In addition, a recent report noted two cases with the association of FIP1L1-PDGFRA-positive chronic eosinophilic leukemia and T-cell lymphoblastic lymphoma (T-LBL). We report here the only third case of synchronous chronic eosinophilic leukemia and T-LBL, both associated with a FIP1L1-PDGFRA fusion transcript, confirming the occurrence of such disease and suggesting a clonal proliferation with two lines of differentiation probably arising from a primitive multipotent medullary stem cell.
...
PMID:Synchronous FIP1L1-PDGFRA-positive chronic eosinophilic leukemia and T-cell lymphoblastic lymphoma: a bilineal clonal malignancy. 1802 20

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.
...
PMID:[Chronic eosinophilic leukemia with complex karyotypic abnormalities including trisomy 8]. 1870 84

Hematological disorders are the third cause of hypereosinophilia, after allergic and parasitic diseases. Hematological disorders associated with hypereosinophilias can be classified as clonal, reactive or idiopathic, and recently the improvements of cytogenetic, molecular biology and immunology have allowed to revisit numerous cases previously diagnosed as idiopathic hypereosinophilic syndrome. Reactive eosinophilias are mainly associated with lymphoma or abnormal, often clonal T lymphoid population. Clonal eosinophilia is related either to various myeloid malignancies or to a genuine myeloproliferative disorder from the eosinophile lineage, the so-called chronic eosinophilic leukaemia. Chronic eosinophilic leukaemia can be associated with recurrent genes rearrangements involving PDGFRA, PDGFRB and FGFR1 or with clonal abnormalities not yet categorized. Idiopathic hypereosinophilic syndrome remains an exclusive diagnosis in presence of moderate or severe unexplained eosinophilia with target organ damage. The purpose of the diagnostic work-up of hypereosinophilic syndrome is to evidence either an abnormal T cell population or a clonal haematopoiesis. Imatinib mesylate dramatically improves chronic eosinophilic leukaemias associated with PDGFR abnormalities, while corticosteroids are still the main treatment for the other patients. In a near future, advances could arise from identification of new genes involved in clonal eosinophilia or in alternative therapy such as the anti-IL-5 antibodies.
...
PMID:[Hematological disorders and hypereosinophilias]. 1920 11

Chronic eosinophilic leukemia (CEL) is a rare myeloproliferative neoplasm characterized by the FIP1L1-PDGFRA fusion gene, variant PDGFRA fusions or other genetic lesions. Most FIP1L1-PDGFRA positive patients enjoy durable and complete molecular responses to low-dose imatinib (Glivec/Gleevec). However, resistance mediated by a T674I mutation in the ATP-binding pocket of PDGFRA has been reported in advanced disease, and sorafenib, a potent inhibitor of RAF-1, B-RAF, VEGFR and PDGFR, is active against this mutant in vitro. We describe a case of FIP1L1-PDGFRalpha T674I CEL in blast crisis that responded to sorafenib (Nexavar). However, this clinical response was short-lived because of the rapid emergence of a FIP1L1-PDGFRalpha D842V mutant. An N-Nitroso-N-ethylurea-mutagenesis screen indeed identified this mutant as a major sorafenib-resistant mutant. In vitro, the novel FIP1L1-PDGFRalpha D842V mutant is highly resistant to sorafenib, imatinib, dasatinib (Sprycell) and PKC412 (Midostaurin). Thus, sorafenib is clinically active in imatinib-resistant FIP1L1-PDGFRalpha T674I CEL, but the rapid emergence of other mutants may limit the response duration. The identification of new PDGFR inhibitors will be required to overcome resistance by this D842V mutant.
...
PMID:FIP1L1-PDGFRalpha D842V, a novel panresistant mutant, emerging after treatment of FIP1L1-PDGFRalpha T674I eosinophilic leukemia with single agent sorafenib. 1921 37

Eosinophilia is a recurrent feature and diagnostic clue in several hematologic malignancies. In stem cell- and myelopoietic neoplasms, eosinophils are derived from the malignant clone, whereas in lymphoid neoplasms and reactive states, eosinophilia is usually triggered by eosinopoietic cytokines. Myeloid neoplasms typically presenting with eosinophilia include chronic myeloid leukemia, chronic eosinophilic leukemia (CEL), other myeloproliferative neoplasms, some acute leukemias, advanced mast cell disorders, and rare forms of myelodysplastic syndromes. Diagnostic evaluations in unexplained eosinophilia have to take these diagnoses into account. In such patients, a thorough hematologic work-up including bone marrow histology and immunohistochemistry, cytogenetics, molecular markers, and a complete staging of potentially affected organ systems has to be initiated. Endomyocardial fibrosis, the most dangerous cardiovascular complication of the hypereosinophilic state, is frequently detected in PDGFR-mutated neoplasms, specifically in FIP1L1/PDGFRA+ CEL, but is usually not seen in other myeloid neoplasms or reactive eosinophilia, even if eosinophilia is recorded for many years. Treatment of hypereosinophilic patients depends on the variant of disease, presence of end organ damage, molecular targets, and the overall situation in each case. In a group of patients, oncogenic tyrosine kinases (TK) such as FIP1L1/PDGFRA, can be employed as therapeutic targets by using imatinib or other TK-blocking agents.
...
PMID:Pathogenesis, classification, and therapy of eosinophilia and eosinophil disorders. 1924 39

According to the 2008 World Health Organization classification system for hematologic malignancies, the myeloproliferative neoplasms (MPN) include chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, mastocytosis, chronic eosinophilic leukemia-not otherwise specified, chronic neutrophilic leukemia, and "MPN, unclassifiable." All of these clinicopathologic entities are characterized by stem cell-derived clonal myeloproliferation, and their phenotypic diversity is ascribed to the occurrence of distinct oncogenic events. In the last 4 years, new JAK2 and MPL mutations have been added to previously described ABL and KIT mutations as molecular markers of disease in MPN. These discoveries have markedly simplified the approach to clinical diagnosis and have also provided molecular targets for the development of small-molecule drugs. In the current article, the authors provide a clinically oriented overview of MPNs in terms of their molecular pathogenesis, classification, diagnosis, and management.
...
PMID:Advances in understanding and management of myeloproliferative neoplasms. 1936 82


<< Previous 1 2 3 4 5 6 7 Next >>

---