Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chronic myeloid disorders (CMD) are collectively characterized by monoclonal myeloproliferation that involves multiple lineages, retains a variable degree of cellular maturation, and has the potential to undergo clonal evolution. However, monoclonal hematopoiesis is neither essential nor specific to CMD. Morphologic and cytogenetic characteristics allow a working classification of these disorders that is clinically useful. There are four major divisions: chronic myeloid leukemia (CML), which is easily identified by the presence of the Philadelphia chromosome (or its molecular equivalent); the myelodysplastic syndromes (MDS), which are characterized by trilineage dysplasia; chronic myeloproliferative diseases (CMPD), which include essential thrombocythemia, polycythemia vera, and agnogenic myeloid metaplasia (AMM); and atypical CMD, which includes chronic neutrophilic leukemia, chronic eosinophilic leukemia, mast cell disease, and myeloid processes that display overlapping features of MDS and CMPD (hybrid CMD). In CMPD, a diagnosis of polycythemia vera requires evidence of an erythropoietin-independent increase in red blood cell mass; the diagnosis of both AMM and essential thrombocythemia requires the exclusion of reactive causes of bone marrow fibrosis and thrombocytosis, respectively. In addition, the Philadelphia chromosome, increased red blood cell mass, and dyserythropoiesis should also be absent. Semin Hematol 38(suppl 2):1-4.
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PMID:Chronic myeloid disorders: Classification and treatment overview. 1124 95

Based on generally accepted criteria and the WHO-classification, a subset of patients with systemic mastocytosis (SM) have (or develop) an associated clonal hematologic non-mast cell lineage disease (SM-AHNMD). We describe a case of SM with coexisting chronic eosinophilic leukemia (SM-CEL). The patient, a 51-year-old male, was first seen in 1992 with small-sized infiltrates of spindle-shaped mast cells in his marrow, and marked eosinophilia. Retrospectively, a CHIC2 deletion and the FIP1L1/PDGFRalpha fusion gene-product were demonstrable by FISH analysis and RT-PCR, respectively. SM-associated organopathy or mediator-related symptoms were not recorded. However, the patient developed cardiomyopathy. Therapy with interferon-alpha, hydroxyurea, and corticosteroids were without effects. By contrast, therapy with imatinib was followed by a fast and sustained response with complete and stable regression of eosinophilia, drop in eosinophil cationic protein, and decrease of serum tryptase to normal levels. This case provides further evidence for the potential of co-existence of SM with a primary eosinophilic disorder (CEL) defined by the FIP1L1/PDGFRalpha fusion gene. Because of the availability of a superior targeted drug (imatinib), it is of importance to screen for FIP1L1/PDGFRalpha in suspected CEL with or without co-existing SM.
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PMID:Systemic mastocytosis (SM) associated with chronic eosinophilic leukemia (SM-CEL): detection of FIP1L1/PDGFRalpha, classification by WHO criteria, and response to therapy with imatinib. 1640 18

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

Before the 1990s, lack of evidence for a reactive cause of hypereosinophilia or chronic eosinophilic leukemia (e.g. presence of a clonal cytogenetic abnormality or increased blood or bone marrow blasts) resulted in diagnosticians characterizing such nebulous cases as 'idiopathic hypereosinophilic syndrome (HES)'. However, over the last decade, significant advances in our understanding of the molecular pathophysiology of eosinophilic disorders have shifted an increasing proportion of cases from this idiopathic HES 'pool' to genetically defined eosinophilic diseases with recurrent molecular abnormalities. The majority of these genetic lesions result in constitutively activated fusion tyrosine kinases, the phenotypic consequence of which is an eosinophilia-associated myeloid disorder. Most notable among these is the recent discovery of the cryptic FIP1L1-PDGFRA gene fusion in karyotypically normal patients with systemic mast cell disease with eosinophilia or idiopathic HES, redefining these diseases as clonal eosinophilias. Rearrangements involving PDGFRA and PDGFRB in eosinophilic chronic myeloproliferative disorders, and of fibroblast growth factor receptor 1 (FGFR1) in the 8p11 stem cell myeloproliferative syndrome constitute additional examples of specific genetic alterations linked to clonal eosinophilia. The identification of populations of aberrant T-lymphocytes secreting eosinophilopoietic cytokines such as interleukin-5 establish a pathophysiologic basis for cases of lymphocyte-mediated hypereosinophilia. This recent revival in understanding the biologic basis of eosinophilic disorders has permitted more genetic specificity in the classification of these diseases, and has translated into successful therapeutic approaches with targeted agents such as imatinib mesylate and recombinant anti-IL-5 antibody.
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PMID:Eosinophilic disorders: molecular pathogenesis, new classification, and modern therapy. 1678 88

The chronic myeloproliferative diseases (CMDs) are a group of conditions characterized by unregulated blood cell production, that due either to excessive numbers of erythrocytes, leukocytes or platelets, or their defective function cause symptoms and signs of fatigue, headache, ruddy cyanosis, hemorrhage, abdominal distension, and the complications of vascular thrombosis. In the late 19th century Vaquez provided the first description of polycythemia vera (PV) and Hueck defined idiopathic myelofibrosis (IMF). In 1920, di Guglielmo established criteria for patients with essential thrombocythemia (ET). In 1951, Dameshek argued that these disorders, along with chronic myelogenous leukemia (CML) display many similar clinical and laboratory features [Dameshek W. Some speculations on the myeloproliferative syndromes. Blood 1951;6:372-5], and grouped them. In 2002, the World Health Organization expanded the definition of CMDs to also include chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES) and systemic mast cell disorder (SMCD) [Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100:2292-302]. While the molecular pathogenesis of CML is well known [Melo JV, Deininger MW. Biology of chronic myelogenous leukemia-signaling pathways of initiation and transformation. Hematol Oncol Clin North Am 2004;18:545-68], and the causes of CEL/HES and SMCD have been identified in about half of all cases [Gotlib J, Cools J, Malone III JM, Schrier SL, Gilliland DG, Coutre SE. The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management. Blood 2004; 103:2879-91; Valent P, Akin C, Sperr WR, Horny HP, Metcalfe DD. Mast cell proliferative disorders: current view on variants recognized by the World Health Organization. Hematol Oncol Clin North Am 2003; 17:1227-41], until very recently the etiologies of the three classically defined CMDs, PV, IMF and ET, were poorly understood. Each of these disorders is characterized by excessive hematopoiesis, a process usually dependent on one or more hematopoietic growth factors (HGFs). This review will focus on how our knowledge of the molecular mechanisms by which HGFs are produced, bind cell surface receptors and transduce survival and proliferative signals have provided the platform on which the multiple origins of CMDs can be understood and novel therapeutic interventions designed.
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PMID:Hematopoietic growth factors, signaling and the chronic myeloproliferative disorders. 1705 68

The 2001 World Health Organization (WHO) treatise on the classification of hematopoietic tumors lists chronic myeloproliferative diseases (CMPDs) as a subdivision of myeloid neoplasms that includes the four classic myeloproliferative disorders (MPDs)-chronic myelogenous leukemia, polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF)-as well as chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES) and 'CMPD, unclassifiable'. In the upcoming 4th edition of the WHO document, due out in 2008, the term 'CMPDs' is replaced by 'myeloproliferative neoplasms (MPNs)', and the MPN category now includes mast cell disease (MCD), in addition to the other subcategories mentioned above. At the same time, however, myeloid neoplasms with molecularly characterized clonal eosinophilia, previously classified under CEL/HES, are now removed from the MPN section and assembled into a new category of their own. The WHO diagnostic criteria for both the classic BCR-ABL-negative MPDs (that is PV, ET and PMF) and CEL/HES have also been revised, in the 2008 edition, by incorporating new information on their molecular pathogenesis. The current review highlights these changes and also provides diagnostic algorithms that are tailored to routine clinical practice.
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PMID:Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. 1841 5

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.
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PMID:Synchronous FIP1L1-PDGFRA-positive chronic eosinophilic leukemia and T-cell lymphoblastic lymphoma: a bilineal clonal malignancy. 1802 20

Hypereosinophilic syndrome (HES), chronic eosinophilic leukemia (CEL), and mast cell disease (MCD) are all considered myeloproliferative neoplasms, and diagnosis in each instance requires bone marrow examination with cytogenetic and molecular studies. HES should be distinguished from both molecularly defined and otherwise uncategorized CEL. The genes that are mutated in molecularly defined CEL include those that encode for platelet-derived growth factor receptors A and B and for fibroblast growth factor receptor 1. Diagnosis of MCD is facilitated by tryptase immunostaining and immunophenotyping to detect abnormal CD25-positive mast cells. Mutation screening for KITD816V is also advised but is not essential for the diagnosis of MCD. Asymptomatic patients with HES and no evidence of organ damage do not necessarily require immediate therapy. The same is true for patients with indolent MCD. At present, effective cytoreductive drugs for HES include corticosteroids, interferon-alpha (IFN-alpha), and hydroxyurea, imatinib for platelet-derived growth factor receptor A or B-rearranged CEL imatinib, and for MCD IFN-alpha and cladribine. In addition, a number of new drugs are currently being tested for their safety and efficacy in all 3 disorders.
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PMID:Hypereosinophilic syndrome, chronic eosinophilic leukemia, and mast cell disease. 1803 76

Expression of the fusion gene FIP1-like 1/platelet-derived growth factor receptor alpha (FIP1L1/PDGFRalpha, F/P) and dysregulated c-kit tyrosine kinase activity are associated with systemic mastocytosis (SM) and chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (HES). We analyzed SM development and pathogenesis in a murine CEL model induced by F/P in hematopoietic stem cells and progenitors (HSCs/Ps) and T-cell overexpression of IL-5 (F/P-positive CEL mice). These mice had more mast cell (MC) infiltration in the bone marrow (BM), spleen, skin, and small intestine than control mice that received a transplant of IL-5 transgenic HSCs/Ps. Moreover, intestinal MC infiltration induced by F/P expression was severely diminished, but not abolished, in mice injected with neutralizing anti-c-kit antibody, suggesting that endogenous stem cell factor (SCF)/c-kit interaction synergizes with F/P expression to induce SM. F/P-expressing BM HSCs/Ps showed proliferation and MC differentiation in vitro in the absence of cytokines. SCF stimulated greater migration of F/P-expressing MCs than mock vector-transduced MCs. F/P-expressing bone marrow-derived mast cells (BMMCs) survived longer than mock vector control BMMCs in cytokine-deprived conditions. The increased proliferation and survival correlated with increased SCF-induced Akt activation. In summary, F/P synergistically promotes MC development, activation, and survival in vivo and in vitro in response to SCF.
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PMID:FIP1L1/PDGFRalpha synergizes with SCF to induce systemic mastocytosis in a murine model of chronic eosinophilic leukemia/hypereosinophilic syndrome. 1877

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.
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PMID:Pathogenesis, classification, and therapy of eosinophilia and eosinophil disorders. 1924 39


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