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)

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

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

TET2 (TET oncogene family member 2) is a candidate tumor suppressor gene located at chromosome 4q24, and was recently reported to be mutated in approximately 14% of patients with JAK2V617F-positive myeloproliferative neoplasms. We used high-throughput DNA sequence analysis to screen for TET2 mutations in bone marrow-derived DNA from 48 patients with systemic mastocytosis (SM), including 42 who met the 2008 WHO (World Health Organization) diagnostic criteria for SM and 6 with FIP1L1-PDGFRA. Twelve (29%) SM, but no FIP1L1-PDGFRA patients, had TET2 mutations. A total of 17 mutations (13 frameshift, 2 nonsense and 2 missense) were documented in 2 (15%) of 13 indolent SM patients, 2 (40%) of 5 aggressive SM, and 8 (35%) of 23 SM associated with a clonal non-mast cell-lineage hematopoietic disease (P=0.52). KITD816V was detected by PCR sequencing in 50 or 20% of patients with or without TET2 mutation (P=0.05), respectively. Multivariable analysis showed a significant association between the presence of TET2 mutation and monocytosis (P=0.0003) or female sex (P=0.05). The association with monocytosis was also observed in non-indolent SM (n=29), in which the presence of mutant TET2 did not affect survival (P=0.98). We conclude that TET2 mutations are frequent in SM, segregate with KITD816V and influence phenotype without necessarily altering prognosis.
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PMID:Frequent TET2 mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. 1926 99

The first formal classification of chronic myeloid neoplasms is credited to William Dameshek, who in 1951 described the concept of "myeloproliferative disorders (MPD)" by grouping together chronic myelogenous leukemia, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2001 World Health Organization (WHO) classification of myeloid malignancies included these MPDs under the broader category of chronic myeloproliferative diseases (CMPD), which also included chronic neutrophilic leukemia, chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES), and "CMPD, unclassifiable." The revised 2008 WHO classification system featured the following changes: 1) the term "CMPD" was replaced by "myeloproliferative neoplasm (MPN)," 2) mast cell disease was formally included under the category of MPN, and 3) the subcategory of CEL/HES was reorganized into "CEL not otherwise specified (CEL-NOS)" and "myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1"; CEL-NOS remained a subcategory of "MPN," whereas the latter neoplasms were now assigned a new category of their own. Furthermore, diagnostic criteria for PV, ET, and PMF were revised by incorporating recently described molecular markers (eg, JAK2 and MPL mutations) as well as underscoring the role of histology in differentiating reactive from clonal myeloproliferations. As a result, red cell mass measurement is no longer necessary for the diagnosis of PV, and ET can now be diagnosed at a lower platelet count threshold. The revised WHO document continues to promote the recognition of histologic categories as a necessary first step toward the genetic characterization of myeloid malignancies.
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PMID:The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos. 1947 96

The chronic myeloproliferative disorders (MPDs) include the spectrum of clonal hematopoietic stem cell disorders whose phenotype derive from the primary cell expanded in a proliferative state. The MPDs (which include polycythemia vera (PV), essential thrombocythemia (ET), chronic eosinophilic leukemia (CEL), primary myelofibrosis (PMF), chronic myelomonocytic leukemia (CMML), and systemic mast cell disease (SMCD)) exclude chronic myeloid leukemia (CML) because of the pathognomic importance of the BCR-ABL translocation for the diagnosis and treatment of this disorder with imatinib mesylate. Empiric use of imatinib mesylate against the spectrum of BCR-ABL negative MPDs has had mixed results. Significant benefits were obtained when empiric use of imatinib in CEL and CMML led to significant clinical benefit and the discovery of the role of rearrangements of the platelet derived growth factor receptor -alpha (PDGFRa-FIP1L1 in CEL and SMCD) and -beta (PDGFRb through TEL-PDGFRb) for CMML). Empiric use of imatinib in PMF has been disappointing, and in PV quite modest. Although next generation Abelson kinase inhibitors such as dasatinib or nilotinib may expand the role for these agents in MPDs, targeted inhibition of the mutant kinase JAK2(V617F) is more likely to make significant therapeutic gains in the classic MPDs of PV, ET, and PMF.
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PMID:Imatinib and tyrosine kinase inhibition, in the management of BCR-ABL negative myeloproliferative disorders. 1970 23

In a substantial number of patients with systemic mastocytosis (SM), an associated clonal haematological non-mast cell lineage disease (AHNMD) is detectable. Although most of these patients display KIT mutations, especially KIT(D816V), little is known about their exact frequency and their distribution in AHNMD subtypes. We examined 48 patients with SM-AHNMD for the presence of mutant KIT in the SM and AHNMD components of the disease. Mast cells and AHNMD cells were obtained from immunostained bone marrow sections by laser microdissection and examined by melting point analysis of nested-PCR products. KIT(D816V) was found in AHNMD cells in the vast majority of patients with SM-chronic myelomonocytic leukaemia (CMML, 89%). Unexpectedly, KIT(D816V) was far less frequently detectable in AHNMD cells in patients with SM-myeloproliferative neoplasm (MPN, 20%) and SM-acute myeloid leukaemia (AML, 30%). None of the patients with lymphoproliferative AHNMDs displayed KIT codon 816 mutations in AHNMD cells (0/8). In FIP1L1/PDGFRA-positive chronic eosinophilic leukaemia (CEL), neither the SM nor the CEL component of the disease exhibited the KIT mutation. Our findings demonstrate that KIT codon 816 mutations are variably present in AHNMD cells in patients with SM-AHNMD, depending on the subtype of AHNMD. The high frequency of KIT(D816V) in neoplastic mast cells and leukaemic myelomonocytic cells in SM-CMML may point to a common precursor in these patients, and may have implications for the biology of the disease and the development of KIT-targeting therapies.
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PMID:Variable presence of KITD816V in clonal haematological non-mast cell lineage diseases associated with systemic mastocytosis (SM-AHNMD). 2011 69

Since the identification of the FIP1L1/PDGFRA fusion gene as a pathogenic cause of the hypereosinophilic syndrome (HES), the importance of the molecular classification of HES leading to the diagnosis of chronic eosinophilic leukemia (CEL) has been recognized. As a result, a new category, 'myeloid and lymphoid neoplasm with eosinophilia and abnormalities in PDGFRA, PDGFRB or FGFR1', has recently been added to the new WHO criteria for myeloid neoplasms. FIP1L1/PDGFR alpha-positive disorders are characterized by clonal hypereosinophilia, multiple organ dysfunctions due to eosinophil infiltration, systemic mastocytosis (SM) and a dramatic response to treatment with imatinib mesylate. A murine HES/CEL model by the introduction of FIP1L1/PDGFR alpha and IL-5 overexpression also shows SM, representing patients with FIP1L1/PDGFR alpha-positive HES/CEL/SM. The murine model and the in vitro development system of FIP1L1/PDGFR alpha-positive mast cells revealed the interaction between FIP1L1/PDGFR alpha, IL-5 and stem cell factor in the development of HES/CEL/SM. Current findings of FIP1L1/PDGFR alpha-positive HES/CEL are reviewed focusing on aberrant mast cell development leading to SM.
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PMID:FIP1L1/PDGFR alpha-associated systemic mastocytosis. 2052 72

Systemic mastocytosis (SM) is a heterogeneous disease, vast majority of these patients have a gain of function mutation in the gene encoding the tyrosine kinase KIT (KIT(D816V)). A small subset of SM patients with KIT(D816V) mutation require cytoreductive therapy. In these patients, tyrosine kinase inhibitors (TKIs) have been actively investigated over the last decade because of codon 816 KIT mutations causing constitutive activation of tyrosine kinase activity of the molecule. The main question has been whether the success story with imatinib in chronic myeloid leukemia (CML), another disease associated with a constitutively active tyrosine kinase, could be mimicked in mastocytosis. However, the results from various TKIs in SM with KIT(D816V) mutation have been disappointing to date. Only a few of the TKIs sufficiently block KIT(D816V) activity and have shown promising clinical results. The data from these studies indicate that, apart from KIT(D816V), other kinase targets and target pathways may play a role in disease evolution and progression, especially in patients with SM with an associated clonal hematological non-mast cell lineage disease (SM-AHNMD). Imatinib is effective in patients with increased mast cells and eosinophils associated with FIP1L1/PDGFRA+ (e.g., myeloid neoplasm with eosinophilia and rearrangement of PDGFRA) or rare patients with SM associated with KIT mutations outside of exon 17. This review will focus on the KIT receptor, KIT mutations, and the effects of the mutations in SM. The preclinical and clinical activities of FDA approved TKIs (for CML) as well as novel TKIs in SM will be evaluated.
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PMID:Tyrosine kinase inhibitors in the treatment of systemic mastocytosis. 2164 42


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