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)

Although KIT mutations are present in 20-25% of cases of t(8;21)(q22;q22) acute myeloid leukemia (AML), concurrent development of systemic mastocytosis (SM) is exceedingly rare. We examined the clinicopathologic features of SM associated with t(8;21)(q22;q22) AML in ten patients (six from our institutions and four from published literature) with t(8;21) AML and SM. In the majority of these cases, a definitive diagnosis of SM was made after chemotherapy, when the mast cell infiltrates were prominent. Deletion 9q was an additional cytogenetic abnormality in four cases. Four of the ten patients failed to achieve remission after standard chemotherapy and seven of the ten patients have died of AML. In the two patients who achieved durable remission after allogeneic hematopoietic stem cell transplant, recipient-derived neoplastic bone marrow mast cells persisted despite leukemic remission. SM associated with t(8;21) AML carries a dismal prognosis; therefore, detection of concurrent SM at diagnosis of t(8;21) AML has important prognostic implications.
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PMID:Systemic mastocytosis associated with t(8;21)(q22;q22) acute myeloid leukemia. 1966 20

A case of systemic mastocytosis associated with a clonal haematological non-mast cell lineage disease (SM-AHNMD), where the associated disease is acute erythroid leukaemia (erythroid/myeloid type), is reported. Interestingly, molecular studies showed the KIT(D816V+) mutation not only in the mast cells, but also in the myeloid blast population and the leukaemic erythroid cells. As is the case with most erythroid leukaemias, the patient had a very aggressive clinical course and died shortly after diagnosis. It is believed that this is the first reported case of systemic mastocytosis with erythroid leukaemia where the KIT(D816V+) mutation was detected in all three cell types. Molecular findings provide evidence for derivation of these seemingly morphologically distinct lesions from the same clonal precursor cell. From a practice standpoint, this case illustrates the importance of definitively diagnosing the associated non-mast cell lineage disease due to its prognostic implications.
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PMID:KIT(D816V+) systemic mastocytosis associated with KIT(D816V+) acute erythroid leukaemia: first case report with molecular evidence for same progenitor cell derivation. 1972 59

A 15-year-old female domestic, medium-haired cat presented to the referring veterinarian with a 2-month history of multiple, raised, disseminated, nodular skin lesions. A biopsy of 1 of the lesions was submitted to the Oklahoma Animal Disease Diagnostic Laboratory for evaluation. Histologically, there were multiple dermal nodules composed of sheets of neoplastic round cells. Multifocally, the neoplastic cells formed multiple small clusters of 3 to 5 cells within the epidermis. Distinct cytoplasmic granules were evident within the neoplastic cells with toluidine blue and Giemsa stains. The neoplastic cells were immunoreactive for c-KIT and lacked immunoreactivity for cluster of differentiation 3 with immunohistochemistry. Based on these findings, multiple epitheliotropic cutaneous mast cell tumors were diagnosed. The cat's health declined rapidly despite aggressive treatment, and the animal was humanely euthanatized. A complete necropsy revealed sheets of similar neoplastic mast cells within the spleen, liver, and individual cells scattered within the bone marrow. Exon 11 of the c-KIT messenger RNA from 1 of the cutaneous masses and the spleen was amplified with reverse transcription polymerase chain reaction, sequenced, and compared with the published c-KIT messenger RNA sequence from fetal cat tissues. The maximum identity was 100% for both tissue samples. To the authors' knowledge, the present report is the first to describe disseminated cutaneous mast cell tumors with epitheliotropism and systemic mastocytosis in a domestic cat.
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PMID:Disseminated cutaneous mast cell tumors with epitheliotropism and systemic mastocytosis in a domestic cat. 1973 71

The purpose of the current study was to investigate the mutation status of KIT in feline mast cell tumours (MCTs) and to examine the effects of tyrosine kinase inhibition on the phosphorylation of mutant kit in vitro and in clinical cases of cats. Sequence analysis of KIT identified mutations in 42/62 MCTs (67.7%). The vast majority of the mutations were distributed in exons 8 and 9, both of which encode the fifth immunoglobulin-like domain (IgD) of kit. All five types of kit with a mutation in the fifth IgD were then expressed in 293 cells and examined for phosphorylation status. The mutant kit proteins showed ligand-independent phosphorylation. The tyrosine kinase inhibitor imatinib mesylate suppressed the phosphorylation of these mutant kit proteins in transfectant cells. In a clinical study of 10 cats with MCTs, beneficial response to imatinib mesylate was observed in 7/8 cats that had a mutation in the fifth IgD of kit in tumour cells. Mutations in the fifth IgD of kit thus appear to be common and potentially sensitive to imatinib mesylate in feline MCTs. These data provide an in vivo model for paediatric mastocytosis where mutations in the fifth IgD of kit also occur.
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PMID:Mutations in the fifth immunoglobulin-like domain of kit are common and potentially sensitive to imatinib mesylate in feline mast cell tumours. 1980 53

In addition to regulating mast cell homeostasis, the activation of KIT following ligation by stem cell factor promotes a diversity of mast cell responses, including cytokine production and chemotaxis. Although we have previously defined a role for the mammalian target of rapamycin complex 1 in these responses, it is clear that other signals are also required for maximal KIT-dependent cytokine production and chemotaxis. In this study, we provide evidence to support a role for glycogen synthase kinase 3beta (GSK3beta) in such regulation in human mast cells (HuMCs). GSK3beta was observed to be constitutively activated in HuMCs. This activity was inhibited by knockdown of GSK3beta protein following transduction of these cells with GSK3beta-targeted shRNA. This resulted in a marked attenuation in the ability of KIT to promote chemotaxis and, in synergy with FcepsilonRI-mediated signaling, cytokine production. GSK3beta regulated KIT-dependent mast cell responses independently of mammalian target of rapamycin. However, evidence from the knockdown studies suggested that GSK3beta was required for activation of the MAPKs, p38, and JNK and downstream phosphorylation of the transcription factors, Jun and activating transcription factor 2, in addition to activation of the transcription factor NF-kappaB. These studies provide evidence for a novel prerequisite priming mechanism for KIT-dependent responses regulated by GSK3beta in HuMCs.
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PMID:Glycogen synthase kinase 3beta activation is a prerequisite signal for cytokine production and chemotaxis in human mast cells. 2000 84

KIT activation, through binding of its ligand, stem cell factor, is crucial for normal mast cell growth, differentiation, and survival. Furthermore, KIT may also contribute to mast cell homing and cytokine generation. Activating mutations in KIT lead to the dysregulated mast cell growth associated with the myeloproliferative disorder, mastocytosis. We investigated the potential of downregulating such responses through mast cell inhibitory receptor activation. In this study, we report that the B cell-associated ITIM-containing inhibitory receptor, CD72, is expressed in human mast cells. Ligation of CD72 with the agonistic Ab, BU40, or with recombinant human CD100 (rCD100), its natural ligand, induced the phosphorylation of CD72 with a resulting increase in its association with the tyrosine phosphatase SH2 domain-containing phosphatase-1. This, in turn, resulted in an inhibition of KIT-induced phosphorylation of Src family kinases and extracellular-regulated kinases (ERK1/2). As a consequence of these effects, KIT-mediated mast cell proliferation, chemotaxis, and chemokine production were significantly reduced by BU40 and rCD100. Furthermore, BU40 and rCD100 also downregulated the growth of the HMC1.2 human mast cell line. Thus, targeting CD72 may provide a novel approach to the suppression of mast cell disease such as mastocytosis.
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PMID:CD72 negatively regulates KIT-mediated responses in human mast cells. 2010 Sep 31

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

Adult mastocytosis is usually persistent and caused by c-KIT codon 816-activating mutations. Pediatric mastocytosis is often transient, and the molecular mechanism driving mast cell proliferation in pediatric cases remains unclear. In this issue, Bodemer et al. report novel c-KIT mutations in a large percentage of pediatric cases, identifying both similarities and fundamental differences in the mechanisms causing adult and pediatric mastocytosis.
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PMID:KIT masters mast cells in kids, too. 1986

Feline cutaneous mast cell tumors (MCTs) have been histologically classified as mastocytic (well differentiated or pleomorphic) and atypical/poorly granulated. Their biologic behavior ranges from benign to malignant, but prognostic factors are not well defined. Histologic classification, number of tumors, mitotic index, cytoplasmic granularity, and infiltration by eosinophils or lymphocytes were evaluated retrospectively in 25 feline cutaneous MCTs. Immunohistochemistry was applied to assess KIT (CD117) pattern and immunoreactivity score, telomerase expression (human telomerase reverse transcriptase), and proliferation index (MIB-1/Ki67 index). Case outcome was obtained via telephone interviews. The tumors comprised 15 mastocytic well-differentiated, 7 mastocytic pleomorphic, and 3 atypical/poorly granulated MCTs. Immunohistochemically, CD117 was expressed in 13 of 25 tumors (52%), and telomerase reverse transcriptase was expressed in 15 of 22 (68%), with no correlation to histologic classification. Mitotic index, KIT immunoreactivity score, and Ki67 index were significantly higher in mastocytic pleomorphic MCTs than in the other 2 categories. Five cats (20%) died of tumor-related causes. Multiplicity of lesions, pleomorphic phenotype, KIT immunoreactivity score, and mitotic and Ki67-indices correlated with an unfavorable outcome. Mitotic index was the strongest predictive variable. These results suggest that histologic classification, CD117/KIT immunohistochemistry, and proliferation indices may help to identify potentially aggressive cases of feline cutaneous MCT. Aberrant KIT protein localization and telomerase immunoreactivity warrant further exploration as potential prognostic markers.
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PMID:Prognostic value of histologic and immunohistochemical features in feline cutaneous mast cell tumors. 2041 69

Compared with adults, pediatric mastocytosis has a relatively favorable prognosis. Interestingly, a difference was also observed in the status of c-kit mutations according to the age of onset. Although most adult patients have a D(816)V mutation in phosphotransferase domain (PTD), we have described that half of the children carry mutations in extracellular domain (ECD). KIT-ECD versus KIT-PTD mutants were introduced into rodent Ba/F3, EML, Rat2, and human TF1 cells to investigate their biologic effect. Both ECD and PTD mutations induced constitutive receptor autophosphorylation and ligand-independent proliferation of the 3 hematopoietic cells. Unlike ECD mutants, PTD mutants enhanced cluster formation and up-regulated several mast cell-related antigens in Ba/F3 cells. PTD mutants failed to support colony formation and erythropoietin-mediated erythroid differentiation. ECD and PTD mutants also displayed distinct whole-genome transcriptional profiles in EML cells. We observed differences in their signaling properties: they both activated STAT, whereas AKT was only activated by ECD mutants. Consistently, AKT inhibitor suppressed ECD mutant-dependent proliferation, clonogenicity, and erythroid differentiation. Expression of myristoylated AKT restored erythroid differentiation in EML-PTD cells, suggesting the differential role of AKT in those mutants. Overall, our study implied different pathogenesis of pediatric versus adult mastocytosis, which might explain their diverse phenotypes.
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PMID:Pediatric mastocytosis-associated KIT extracellular domain mutations exhibit different functional and signaling properties compared with KIT-phosphotransferase domain mutations. 2048 85


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