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

Both stem cells and mast cells express c-kit and proliferate after exposure to c-kit ligand. Mutations in c-kit may enhance or interfere with the ability of c-kit receptor to initiate the intracellular pathways resulting in cell proliferation. These observations suggested to us that mastocytosis might in some patients result from mutations in c-kit. cDNA synthesized from peripheral blood mononuclear cells of patients with indolent mastocytosis, mastocytosis with an associated hematologic disorder, aggressive mastocytosis, solitary mastocytoma, and chronic myelomonocytic leukemia unassociated with mastocytosis was thus screened for a mutation of c-kit. This analysis revealed that four of four mastocytosis patients with an associated hematologic disorder with predominantly myelodysplastic features had an A-->T substitution at nt 2468 of c-kit mRNA that causes an Asp-816-->Val substitution. One of one patient examined who had mastocytosis with an associated hematologic disorder had the corresponding mutation in genomic DNA. Identical or similar amino acid substitutions in mast cell lines result in ligand-independent autophosphorylation of the c-kit receptor. This mutation was not identified in the patients within the other disease categories or in 67 of 67 controls. The identification of the point mutation Asp816Val in c-kit in patients with mastocytosis with an associated hematologic disorder provides insight not only into the pathogenesis of this form of mastocytosis but also into how hematopoiesis may become dysregulated and may serve to provide a means of confirming the diagnosis, assessing prognosis, and developing intervention strategies.
 ...
PMID:Identification of a point mutation in the catalytic domain of the protooncogene c-kit in peripheral blood mononuclear cells of patients who have mastocytosis with an associated hematologic disorder. 747 40

Systemic mast cell disease (SMCD) has a highly variable clinical expression and course. That SMCD is associated with hematologic disorders has been widely described. We report an unusual case of systemic mast cell disease and concurrent chronic myelomonocytic leukemia in a 60 year old male.
 ...
PMID:Systemic mast cell disease with marrow and splenic involvement associated with chronic myelomonocytic leukemia. 1003 40

Patients with systemic mast cell (MC) disease, but not those with cutaneous mastocytosis, are at a high risk (10-30%) to develop life-threatening myelogenous malignancies. In a significant proportion of cases, myeloid leukemias occur. Using conventional criteria, such leukemias resemble acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or myelomonocytic leukemia (CMML). Mast cell leukemia (MCL) may also occur. Myeloid leukemias (AML, CML, CMML) can develop in indolent or aggressive mastocytosis (skin lesions present or absent) with a variable prephase of MC disease. By contrast, MCL (typically without skin lesions) often develops on a "de novo" basis, and, if at all recognized, a prephase resembling (malignant) mastocytosis, is short. MCL differs from myeloid leukemias (AML, CML, CMML) by morphologic and phenotypic cellular characteristics. In fact, MCL are strongly tryptase-positive, c-kit-positive, myeloperoxidase (MPO) -negative neoplasms with variable metachromasia and chloroacetate esterase expression, whereas an MPO-positive, tryptase-negative phenotype supports the diagnosis of a myeloid non-MC lineage disease. Thus, MCL, but also myeloid non-MC lineage leukemias can develop in patients with (systemic) mastocytosis. Little is known, however, about the pathophysiologic basis of co-evolution. In the present article, the concomitant occurrence of mastocytosis and leukemia is discussed in the light of the literature and of concepts proposed to explain the biologic basis of this phenomenon.
 ...
PMID:Clinical and biologic diversity of leukemias occurring in patients with mastocytosis. 1104 8

The majority of patients with systemic mastocytosis with associated clonal, hematological non-mast cell lineage disease (SM-AHNMD) have a myeloid stem cell malignancy including myelodysplastic syndromes (MDS), myelodysplastic/myeloproliferative disorders, acute myeloid leukemia (AML), or chronic myeloproliferative disease. The clinicopathologic features of SM-AHNMD have not been fully characterized. We describe seven cases of this entity: 3 with MDS, 3 with AML, and 1 with chronic myelomonocytic leukemia. In the majority of cases, SM was diagnosed concurrently with the myeloid malignancy and aberrant mast cell morphology was observed. The commonly described c-kit enzymatic site mutation Asp816Val was detected only in 2 cases, while 3 patients carried the Asp816His mutation. Among the 3 cases with AML, 2 patients carried the translocation t(8;21). On the basis of our results and other reported cases, there appears to be a specific association between SM and AML with t(8;21). Concurrent occurrence of SM may define a subset of patients with de novo AML and other myeloid malignancies who have an adverse prognosis. As clinically effective tyrosine kinase inhibitors that inhibit enzymatic-type c-kit mutations are being developed, detection of mast cell proliferation associated with myeloid malignancy may have important therapeutic implications.
 ...
PMID:Systemic mastocytosis with associated clonal hematological non-mast-cell lineage disease: analysis of clinicopathologic features and activating c-kit mutations. 1270 Nov 14

We screened 115 patients with chronic myeloid disorders (CMD) for known flt-3 and c-kit mutations in both the juxtamembrane (JM) and the activation loop (AL) domains. None of the patients displayed flt-3 (JM or AL) or c-kit JM mutations. However, the c-kit AL (D816V) mutation was detected in 5 of 16 patients with systemic mast cell disease (SMCD) but in none of the remaining 99 patients with other CMD. In SMCD, the presence of D816V mutation was significantly associated with advanced age, an aggressive clinical course, increased bone marrow mast cell content, and chronic myelomonocytic leukemia.
 ...
PMID:Flt-3 and c-kit mutation studies in a spectrum of chronic myeloid disorders including systemic mast cell disease. 1280 32

The new WHO classification is based on the principles of REAL classification of lymphoma and expands to myeloid, mast cell and histiocytic/dendritic neoplasms. The distinct diseases are defined according to a combination of morphology, immunophenotype, genetic features, and clinical syndromes, and the cell origin is postulated. Lymphatic leukemia is included in lymphoma. The lymphoid malignancies are grouped into B cell lymphoma, T/NK cell lymphoma and Hodgkin lymphoma, and the myeloid neoplasm are grouped into 4 categories; chronic myeloproliferative diseases(chronic myelogeneous leukemia, polycythemia vera, chronic idiopathic myelofibrosis, essential thrombocythemia etc.), myelodysplastic/myeloproliferative diseases (chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia etc.), myelodysplastic diseases(perfactory anemia, refractory anemia with ringed sideroblasts etc.) and acute myeloid leukemia.
 ...
PMID:[Malignant lymphoma and leukemia concepts in new WHO classification]. 1367 44

The myeloproliferative disorders (MPDs) are chronic malignant conditions originating from the clonal expansion of a multipotential hematopoietic stem cell. These diseases include polycythemia vera (PV), essential thrombocythenia, atypical chronic myeloid leukemia, idiopathic hypereosinophilic syndrome (HES), agnogenic myeloid metaplasia with myelofibrosis, and others. Receptor tyrosine kinases-the platelet-derived growth factor receptors (PDGFRs) and c-Kit-and their respective ligands have been implicated in the pathogenesis of MPDs. For example, a constitutively activated PDGFR fusion tyrosine kinase (FIP1L1-PDGFRA) was identified in some patients with HES, a disease characterized by sustained overproduction of eosinophils that has been classified by the World Health Organization as a chronic subtype of the MPDs. Imatinib is a selective inhibitor of PDGFRs, c-Kit, Abl and Arg protein-tyrosine kinases, as well as Bcr-Abl, the oncogenic tyrosine kinase that causes chronic myeloid leukemia. The efficacy of imatinib in treating HES, systemic mast cell disease, chronic myelomonocytic leukemia associated with PDGFRbeta fusion genes, and (to a lesser extent) PV and idiopathic myelofibrosis was reviewed from institutional experience and a review of the literature. In 3 studies that involved 11 patients with PV, 10 patients had reductions in phlebotomy with imatinib. Eight studies of 42 patients with HES indicated that 70% achieved complete hematologic remissions with imatinib. Four studies of 6 patients with MPD indicated responses with imatinib in 5 patients. Insight into the molecular pathogenesis of MPDs will improve the definitions of different disease categories and suggests that signal transduction inhibition is likely to be an increasingly important treatment option in the future.
 ...
PMID:Beyond chronic myelogenous leukemia: potential role for imatinib in Philadelphia-negative myeloproliferative disorders. 1513 47

Use of the term "idiopathic hypereosinophilic syndrome (HES)" has highlighted our basic lack of understanding of the molecular pathophysiology of eosinophilic disorders. However, over the last 10 years, the study of hypereosinophilia has enjoyed a revival. This interest has been rekindled by two factors: (1) the development of increasingly sophisticated molecular biology techniques that have unmasked recurrent genetic abnormalities linked to eosinophilia, and (2) the successful application of targeted therapy with agents such as imatinib to treat eosinophilic diseases. To date, most of these recurrent molecular abnormalities have resulted in constitutively activated fusion tyrosine kinases whose phenotypic consequence is an eosinophilia-associated myeloid disorder. Most notable among these are rearrangements of platelet-derived growth factor receptors alpha and beta (PDGFRalpha, PDGFRbeta), which define a small subset of patients with eosinophilic chronic myeloproliferative disorders (MPDs) and/or overlap myelodysplastic syndrome/MPD syndromes, including chronic myelomonocytic leukemia. Discovery of the cryptic FIP1L1-PDGFRA gene fusion in cytogenetically normal patients with systemic mast cell disease with eosinophilia or idiopathic HES has redefined these diseases as clonal eosinophilias. A growing list of fibroblast growth factor receptor 1 fusion partners has similarly emerged in the 8p11 myeloproliferative syndromes, which are often characterized by elevated eosinophil counts. Herein the focus is on the molecular gains made in these MPD-type eosinophilias, and the classification and clinicopathological issues related to hypereosinophilic syndromes, including the lymphocyte variant. Success in establishing the molecular basis of a group of once seemingly heterogeneous diseases has now the laid the foundation for establishing a semi-molecular classification scheme of eosinophilic disorders.
 ...
PMID:Molecular classification and pathogenesis of eosinophilic disorders: 2005 update. 1599 22

Myeloid disorders constitute a subgroup of hematological malignancies that is separate from lymphoid disorders. The World Health Organization system for classification of tumors of the hematopoietic system divides myeloid disorders into acute myeloid leukemia and chronic myeloid disorders based on the presence or absence, respectively, of acute myeloid leukemia--defining morphological and cytogenetic features including the presence of 20% or more myeloblasts in either the bone marrow or the peripheral blood. A recently proposed semimolecular classification system for chronic myeloid disorders recognizes 3 broad categories: the myelodysplastic syndrome, classic myeloproliferative disorders (MPD), and atypical MPD. Classic MPD includes polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, and chronic myeloid leukemia. Both myelodysplastic syndrome and BCR/ABL-negative classic MPD were previously discussed as part of the current ongoing symposium on hematological malignancies. The current review focuses on the diagnosis and treatment of both molecularly defined and clinicopathologically assigned categories of atypical MPD: chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, chronic neutrophilic leukemia, chronic basophilic leukemia, chronic eosinophilic leukemia, idiopathic eosinophilia including hypereosinophilic syndrome, systemic mastocytosis, unclassified MPD, and eosinophilic/mast cell disorders associated with mutations of platelet-derived growth factor receptors alpha (PDGFRA) and beta (PDGFRB), FGFR1, and KIT.
 ...
PMID:Atypical myeloproliferative disorders: diagnosis and management. 1661 May 78

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.
 ...
PMID:Imatinib and tyrosine kinase inhibition, in the management of BCR-ABL negative myeloproliferative disorders. 1970 23


1 2 Next >>