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1.
Sci Rep ; 8(1): 17107, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30459395

RESUMO

G-quadruplexes (G4) are secondary nucleic acid structures that have been associated with genomic instability and cancer progression. When present in the promoter of some oncogenes, G4 structures can affect gene regulation and, hence, represent a possible therapeutic target. In this study, RNA-Seq was used to explore the effect of a G4-binding anthraquinone derivative, named AQ1, on the whole-transcriptome profiles of two common cell models for the study of KIT pathways; the human mast cell leukemia (HMC1.2) and the canine mast cell tumor (C2). The highest non-cytotoxic dose of AQ1 (2 µM) resulted in 5441 and 1201 differentially expressed genes in the HMC1.2 and C2 cells, respectively. In both cell lines, major pathways such as cell cycle progression, KIT- and MYC-related pathways were negatively enriched in the AQ1-treated group, while other pathways such as p53, apoptosis and hypoxia-related were positively enriched. These findings suggest that AQ1 treatment induces a similar functional response in the human and canine cell models, and provide news insights into using dogs as a reliable translational model for studying G4-binding compounds.


Assuntos
Antraquinonas/farmacologia , Quadruplex G/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Leucemia de Mastócitos/patologia , Mapas de Interação de Proteínas/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Animais , Cães , Humanos , Técnicas In Vitro , Leucemia de Mastócitos/tratamento farmacológico , Leucemia de Mastócitos/genética , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Células Tumorais Cultivadas
2.
Diagn Pathol ; 13(1): 14, 2018 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-29458385

RESUMO

BACKGROUND: Mast cell leukemia (MCL) is a very rare form of systemic mastocytosis (SM) and accounts for less than 0.5% of all mastocytosis. The diagnosis of MCL requires the presence of SM criteria, accompanied by leukemic infiltrating of atypical mast cells (MCs) in bone marrow (BM), peripheral blood as well as extracutaneous organs. MCL is a fatal disease that almost always behaves aggressively, and the median survival time is only about six months. Herein, we present a rare case of de novo MCL without CD25 expression and KIT mutations. CASE PRESENTATION: A previously healthy 13-year-old boy was referred to our hospital due to incidental discovery of an enlarged right tonsil. Diffuse infiltration of medium-sized hematopoietic blasts was found in his right tonsil, BM and multiple lymph nodes. The neoplastic cell population was subsequently revealed to exhibit differentiation towards the mast cell lineage by expressing CD117 and tryptase, but the cell population lacked expression of CD25/CD2 and the activating mutation of the KIT gene. An abnormal karyotype was identified, but no leukemia-associated fusion genes were found. Involvement of peripheral blood, bone and lung was subsequently demonstrated. The most important differential diagnosis included tryptase-positive (T+) acute myeloid leukemia, myelomastocytic leukemia and basophilic leukemia. The morphological characteristics and infiltrating patterns of the abnormal MCs supported the final diagnosis of MCL. Although intensive chemotherapy and allogeneic stem cell transplants were performed on the patient, he died 18 months after initial presentation. CONCLUSION: Due to its rarity, the diagnosis of MCL without typical immunophenotype and genetic aberrations is particularly challenging. Comprehensive investigation of clinical and pathological features to exclude other T+ myeloid neoplasms is necessary.


Assuntos
Subunidade alfa de Receptor de Interleucina-2/deficiência , Leucemia de Mastócitos/genética , Mutação/genética , Proteínas Proto-Oncogênicas c-kit/genética , Adolescente , Medula Óssea/patologia , Humanos , Imunofenotipagem , Leucemia de Mastócitos/diagnóstico , Masculino , Mastócitos/citologia , Mastocitose/diagnóstico , Mastocitose/genética , Mastocitose Sistêmica/patologia
3.
Ann Hematol ; 97(3): 533-535, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29151134
4.
Ann Biol Clin (Paris) ; 75(6): 689-694, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-29043985

RESUMO

Mast cell leukemia is an extremely rare disease, which belongs to the systemic mastocytosis group (WHO 2016). We are reporting the case of a 79-year-old woman, without any hematological particular history consulting for hyperthermia, repeated malaise and subacute anemia. Her clinical examination was normal. Unusual cells were seen on blood and bone marrow smears. They represent more than 10% of blood nucleated cells end more than 20% of the bone marrow nucleated cells. Bone marrow immunophenotyping was performed to characterize these cells. It revealed a cell subset expressing the surface antigens CD117, CD2 and CD25. This immunophenotypic profile is the hallmark of malignant mast cells. Then mast cell leukemia diagnosis could have been made and KIT gene sequencing highlighted the N822Y mutation in exon 17. The patient was initially treated with midostaurin, a tyrosine kinase inhibitor. Lack of therapeutic response and absence of the KIT D816V mutation led to switch to imatinib, following the latest scientific recommendations.


Assuntos
Anemia/diagnóstico , Células Sanguíneas/patologia , Leucemia de Mastócitos/diagnóstico , Mastócitos/patologia , Mastocitose Sistêmica/diagnóstico , Idoso , Substituição de Aminoácidos , Anemia/sangue , Anemia/genética , Citodiagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Leucemia de Mastócitos/sangue , Leucemia de Mastócitos/genética , Mastocitose Sistêmica/sangue , Mastocitose Sistêmica/genética , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas c-kit/genética
6.
Hum Pathol ; 67: 198-204, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28412213

RESUMO

To the best of our knowledge, this manuscript describes clinical and pathologic findings of the first case of acute mast cell leukemia harboring t(4;5)(q21;q33), compatible with fusion of the PDGFRB gene to a rare partner, PRKG2. Translocation involving the PDGFRB gene is confirmed by fluorescence in situ hybridization study. This case presented a relatively fulminant clinical course with acute mast cell leukemia and "C" findings (cytopenia, hepatosplenomegaly, and weight loss), mast cell sarcoma, and severe basophilia. Despite aggressive presentation initially, the patient responded well to tyrosine kinase inhibitor treatment and is currently in complete remission 33 months after diagnosis. This case significantly extends the disease spectrum associated with PRKG2/PDGFRB fusion gene. Recognizing the whole spectrum of diseases associated with this fusion is critical because tyrosine kinase inhibitor treatment has been exceedingly effective in these patients.


Assuntos
Biomarcadores Tumorais/genética , Cromossomos Humanos Par 4 , Cromossomos Humanos Par 5 , Leucemia de Mastócitos/genética , Translocação Genética , Doença Aguda , Antineoplásicos/uso terapêutico , Biópsia , Proteína Quinase Dependente de GMP Cíclico Tipo II/genética , Fusão Gênica , Predisposição Genética para Doença , Humanos , Mesilato de Imatinib/uso terapêutico , Imuno-Histoquímica , Leucemia de Mastócitos/tratamento farmacológico , Leucemia de Mastócitos/enzimologia , Leucemia de Mastócitos/patologia , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular , Terapia de Alvo Molecular , Fenótipo , Inibidores de Proteínas Quinases/uso terapêutico , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento
7.
Haematologica ; 102(6): 1035-1043, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28255023

RESUMO

Mast cell leukemia is a rare variant of advanced systemic mastocytosis characterized by at least 20% of mast cells in a bone marrow smear. We evaluated clinical and molecular characteristics of 28 patients with (n=20, 71%) or without an associated hematologic neoplasm. De novo mast cell leukemia was diagnosed in 16 of 28 (57%) patients and secondary mast cell leukemia evolving from other advanced systemic mastocytosis subtypes in 12 of 28 (43%) patients, of which 7 patients progressed while on cytoreductive treatment. Median bone marrow mast cell infiltration was 65% and median serum tryptase was 520 µg/L. C-findings were identified in 26 of 28 (93%) patients. Mutations in KIT (D816V, n=19; D816H/Y, n=5; F522C, n=1) were detected in 25 of 28 (89%) patients and prognostically relevant additional mutations in SRSF2, ASXL1 or RUNX1 (S/A/Rpos) in 13 of 25 (52%) patients. Overall response rate in 18 treatment-naïve patients was 5 of 12 (42%) on midostaurin and 1 of 6 (17%) on cladribine, and after switch 1 of 4 (25%) on midostaurin and 0 of 3 on cladribine, respectively. S/A/Rpos adversely affected response to treatment and progression to secondary mast cell leukemia (n=6) or acute myeloid leukemia (n=3) while on treatment (P<0.05). The median overall survival from mast cell leukemia diagnosis was 17 months as compared to 44 months in a control group of 124 patients with advanced systemic mastocytosis but without mast cell leukemia (P=0.03). In multivariate analyses, S/A/Rpos remained the only independent poor prognostic variable predicting overall survival (P=0.007). In conclusion, the molecular signature should be determined in all patients with mast cell leukemia because of its significant clinical and prognostic relevance.


Assuntos
Progressão da Doença , Neoplasias Hematológicas/complicações , Leucemia de Mastócitos/genética , Mutação , Cladribina/uso terapêutico , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Humanos , Leucemia de Mastócitos/complicações , Leucemia de Mastócitos/tratamento farmacológico , Leucemia de Mastócitos/mortalidade , Masculino , Mastocitose Sistêmica/mortalidade , Pessoa de Meia-Idade , Prognóstico , Proteínas Repressoras/genética , Fatores de Processamento de Serina-Arginina/genética , Estaurosporina/análogos & derivados , Estaurosporina/uso terapêutico , Taxa de Sobrevida
9.
Genes Chromosomes Cancer ; 55(4): 389-96, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26865278

RESUMO

Systemic mastocytosis (SM) is characterized by a clonal proliferation of aberrant mast cells within extracutaneous sites. In a subset of SM cases, a second associated hematologic non-mast cell disease (AHNMD) is also present, usually of myeloid origin. Polymerase chain reaction and targeted fluorescence in situ hybridization studies have provided evidence that, in at least some cases, the aberrant mast cells are related clonally to the neoplastic cells of the AHNMD. In this work, a single nucleotide polymorphism microarray (SNP-A) was used to characterize the cytogenetics of the aberrant mast cells from a patient with acute myeloid leukemia and concomitant mast cell leukemia associated with a KIT D816A mutation. The results demonstrate the presence of shared cytogenetic abnormalities between the mast cells and myeloid blasts, as well as additional abnormalities within mast cells (copy-neutral loss of heterozygosity) not detectable by routine karyotypic analysis. To our knowledge, this work represents the first application of SNP-A whole-genome scanning to the detection of shared cytogenetic abnormalities between the two components of a case of SM-AHNMD. The findings provide additional evidence of a frequent clonal link between aberrant mast cells and cells of myeloid AHNMDs, and also highlight the importance of direct sequencing for identifying uncommon activating KIT mutations.


Assuntos
Leucemia de Mastócitos/genética , Leucemia Mieloide Aguda/genética , Mastócitos/patologia , Células Mieloides/patologia , Biópsia , Medula Óssea/patologia , Aberrações Cromossômicas , Células Clonais , Doenças Hematológicas/complicações , Doenças Hematológicas/genética , Doenças Hematológicas/patologia , Humanos , Cariótipo , Leucemia de Mastócitos/patologia , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
10.
Leukemia ; 29(11): 2230-7, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26055303

RESUMO

Advanced systemic mastocytosis (SM) is a life-threatening neoplasm characterized by uncontrolled growth and accumulation of neoplastic mast cells (MCs) in various organs and a poor survival. So far, no curative treatment concept has been developed for these patients. We identified the epigenetic reader bromodomain-containing protein-4 (BRD4) as novel drug target in aggressive SM (ASM) and MC leukemia (MCL). As assessed by immunohistochemistry and PCR, neoplastic MCs expressed substantial amounts of BRD4 in ASM and MCL. The human MCL lines HMC-1 and ROSA also expressed BRD4, and their proliferation was blocked by a BRD4-specific short hairpin RNA. Correspondingly, the BRD4-targeting drug JQ1 induced dose-dependent growth inhibition and apoptosis in HMC-1 and ROSA cells, regardless of the presence or absence of KIT D816V. In addition, JQ1 suppressed the proliferation of primary neoplastic MCs obtained from patients with ASM or MCL (IC50: 100-500 nm). In drug combination experiments, midostaurin (PKC412) and all-trans retinoic acid were found to cooperate with JQ1 in producing synergistic effects on survival in HMC-1 and ROSA cells. Taken together, we have identified BRD4 as a promising drug target in advanced SM. Whether JQ1 or other BET-bromodomain inhibitors are effective in vivo in patients with advanced SM remains to be elucidated.


Assuntos
Epigênese Genética , Leucemia de Mastócitos/genética , Proteínas Nucleares/fisiologia , Fatores de Transcrição/fisiologia , Antígenos CD/análise , Apoptose/efeitos dos fármacos , Azepinas/farmacologia , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Regulação Leucêmica da Expressão Gênica , Humanos , Leucemia de Mastócitos/tratamento farmacológico , Leucemia de Mastócitos/patologia , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Proteínas Proto-Oncogênicas c-kit/fisiologia , Receptores da Transferrina/análise , Tetraspanina 30/análise , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Tretinoína/farmacologia , Triazóis/farmacologia
12.
Crit Rev Oncol Hematol ; 93(2): 75-89, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25305106

RESUMO

Within the last decade, and in particular since 2012, research has greatly extended our understanding of the molecular basis of systemic mast cell activation disease (MCAD). Initial studies demonstrated that somatic mutations in the tyrosine kinase KIT led to the establishment of a clonal mast cell population. Recent studies, in particular those involving next generation sequencing analyses of advanced systemic mastocytosis, have revealed mutations in additional genes. The respective genes encode proteins for various signaling pathways, epigenetic regulators, the RNA splicing machinery, and transcription factors. Although almost all of the detected mutations are somatic in nature, transgenerational transmission of MCAD appears to be quite common. However, the molecular mechanisms underlying genetic predestination, e.g. germline mutations and the contribution of epigenetic processes, still await identification. The aim of the present review is to present and discuss available genetic findings, and to outline the relationship between adult-onset systemic MCAD and childhood-onset mastocytosis, often termed cutaneous mastocytosis, on the basis of current genetic data. Finally, the implications of increased knowledge of the molecular basis of MCAD in terms of diagnostics and therapy are discussed.


Assuntos
Leucemia de Mastócitos/genética , Mastócitos/patologia , Mastocitose Cutânea/genética , Mastocitose Sistêmica/genética , Proteínas Proto-Oncogênicas c-kit/genética , Imunidade Adaptativa , Células Clonais , Epigênese Genética , Expressão Gênica , Humanos , Imunidade Inata , Leucemia de Mastócitos/diagnóstico , Leucemia de Mastócitos/imunologia , Leucemia de Mastócitos/patologia , Mastócitos/imunologia , Mastocitose Cutânea/diagnóstico , Mastocitose Cutânea/imunologia , Mastocitose Cutânea/patologia , Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/imunologia , Mastocitose Sistêmica/patologia , Mutação , Proteínas Proto-Oncogênicas c-kit/imunologia , Processamento de RNA , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia
13.
Ann Hematol ; 94(2): 223-31, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25209843

RESUMO

Mast cell leukemia (MCL) is a rare, life-threatening malignancy defined by a substantial increase in neoplastic mast cells (MCs) in bone marrow (BM) smears, drug-resistance, and a poor prognosis. In most patients, the survival time is less than 1 year. However, exceptional cases may present with a less malignant course. We report on a 49-year-old female patient with MCL diagnosed in 2013. In February 2013, first symptoms, including flushing, headache, and diarrhea, were recorded. In addition, mild anemia was detected. The disease was characterized by a massive increase in well-granulated, mature, and often spindle-shaped MCs (80 %) in BM smears. The serum tryptase level amounted to 332 ng/mL. Like in most other MCL patients, no skin lesions were detected. However, unlike in other patients, tryptase levels remained stable, and no other signs or symptoms of MCL-induced organ damage were found. Sequencing studies revealed an isolated S476I point mutation in KIT but no mutation in codon 816. The patient received histamine receptor blockers but refused cytoreductive therapy. After 9 months, still no progression or organ damage was detected. However, progression with transformation to acute MCL occurred after 12 months. We propose that the chronic type of MCL with stable conditions, absence of organ damage, and a mature MC morphology is recognized as a distinct entity that should be distinguished from the acute variant of MCL.


Assuntos
Leucemia de Mastócitos/genética , Mastócitos/metabolismo , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas c-kit/genética , Exame de Medula Óssea , Proliferação de Células/efeitos dos fármacos , Doença Crônica , Feminino , Humanos , Leucemia de Mastócitos/patologia , Mastócitos/efeitos dos fármacos , Mastócitos/patologia , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/farmacologia
14.
Curr Protein Pept Sci ; 15(1): 36-44, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24555898

RESUMO

The prevalence of cancer in companion animals has increased in the recent decade, making this disease one of the major causes of deaths. As in human medicine, veterinary medicine faces the problem of cancer prevention as well as early diagnosis and effective therapy. Early diagnosis of cancer is crucial for the successful treatment of the disease and there is a need for biomarkers that could be used as a diagnostic tool, and to guide a targeted therapy or monitor a therapeutic response. Proteomic technologies that were introduced to human cancer research over a decade ago provide the opportunity to identify distinct protein patterns for cancer diagnosis and therapy monitoring. These also have potential to be utilised in veterinary medicine. The present paper summarises the current knowledge about proteomic studies on animal cancer biomarker research published to date.


Assuntos
Biomarcadores Tumorais/análise , Leucemia de Mastócitos/diagnóstico , Linfoma/diagnóstico , Neoplasias Mamárias Animais/diagnóstico , Proteínas de Neoplasias/análise , Proteômica/métodos , Animais , Antineoplásicos/farmacologia , Gatos , Cães , Diagnóstico Precoce , Leucemia de Mastócitos/genética , Leucemia de Mastócitos/patologia , Leucemia de Mastócitos/terapia , Linfoma/genética , Linfoma/patologia , Linfoma/terapia , Neoplasias Mamárias Animais/genética , Neoplasias Mamárias Animais/patologia , Neoplasias Mamárias Animais/terapia , Patologia Veterinária , Proteômica/instrumentação , Ovinos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
15.
Ann Hematol ; 93(1): 81-8, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24281161

RESUMO

The activating KIT D816V mutation plays a central role in the pathogenesis, diagnosis, and targeted treatment of systemic mastocytosis (SM). For improved and reliable identification of KIT D816V, we have developed an allele-specific quantitative real-time PCR (RQ-PCR) with an enhanced sensitivity of 0.01-0.1 %, which was superior to denaturing high-performance liquid chromatography (0.5-1 %) or conventional sequencing (10-20 %). Overall, KIT D816 mutations were identified in 146/147 (99 %) of patients (D816V, n = 142; D816H, n = 2; D816Y, n = 2) with SM, including indolent SM (ISM, n = 63, 43 %), smoldering SM (n = 8, 5 %), SM with associated hematological non-mast cell lineage disease (SM-AHNMD, n = 16, 11 %), and aggressive SM/mast cell leukemia ± AHNMD (ASM/MCL, n = 60, 41 %). If positive in BM, the KIT D816V mutation was found in PB of all patients with advanced SM (SM-AHNMD, ASM, and MCL) and in 46 % (23/50) of patients with ISM. There was a strong correlation between the KIT D816V expressed allele burden (KIT D816V EAB) with results obtained from DNA by genomic allele-specific PCR and also with disease activity (e.g., serum tryptase level), disease subtype (e.g., indolent vs. advanced SM) and survival. In terms of monitoring of residual disease, qualitative and quantitative assessment of KIT D816V and KIT D816V EAB was successfully used for sequential analysis after chemotherapy or allogeneic stem cell transplantation. We therefore conclude that RQ-PCR assays for KIT D816V are useful complimentary tools for diagnosis, disease monitoring, and evaluation of prognosis in patients with SM.


Assuntos
Alelos , Mastocitose Sistêmica/genética , Mutação de Sentido Incorreto , Mutação Puntual , Proteínas Proto-Oncogênicas c-kit/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Substituição de Aminoácidos , Biomarcadores , Cromatografia Líquida de Alta Pressão , Diagnóstico Diferencial , Feminino , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/genética , Humanos , Estimativa de Kaplan-Meier , Leucemia de Mastócitos/diagnóstico , Leucemia de Mastócitos/genética , Masculino , Mastocitose Sistêmica/sangue , Mastocitose Sistêmica/diagnóstico , Mastocitose Sistêmica/mortalidade , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Análise de Sequência de DNA , Triptases/sangue
17.
Immunol Res ; 56(1): 155-62, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23504229

RESUMO

To circumvent the costly isolation procedure associated with tissue mast cells, human mast cell lines such as HMC-1 are employed in mastocytosis research, but their relation to mutated mast cells in systemic mastocytosis has not been investigated systematically. In the present study, we determined the transcriptome of HMC-1.2 cells and compared the expression data with those reported in the literature for normal human resting lung and tonsillar mast cells as well as leukocytes from peripheral blood and mononuclear cells from bone marrow aspirates of patients with D816 V-positive systemic mastocytosis. Our results suggest that HMC-1.2 cells are an appropriate model for the investigation of this variant of systemic mast cell activation disease. The data confirm previous suggestions that the pathologically increased activity of mast cells in patients with D816 V-positive systemic mastocytosis can be deduced from the detection of mutation-related changes in the gene expression profile in leukocytes from peripheral blood and in mononuclear cells from bone marrow aspirates. Thus, mutation-related changes of the expression profile can serve as surrogates (besides clustering of mast cells, expression of CD25, and increased release of tryptase) for the presence of the mutation D816 V in tyrosine kinase Kit in patients with systemic mastocytosis according to the WHO criteria. Whether this also holds true for systemic mast cell activation disease caused by other mutations in Kit or other mast cell activity-related genes is a subject for future studies.


Assuntos
Biomarcadores Tumorais/metabolismo , Leucemia de Mastócitos/imunologia , Mastócitos/imunologia , Mastocitose Sistêmica/imunologia , Proteínas Proto-Oncogênicas c-kit/metabolismo , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Proliferação de Células , Estudos de Viabilidade , Perfilação da Expressão Gênica/métodos , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Leucemia de Mastócitos/genética , Pulmão/citologia , Mastocitose Sistêmica/genética , Mutação/genética , Tonsila Palatina/citologia , Proteínas Proto-Oncogênicas c-kit/genética , Triptases/metabolismo
18.
Eur J Haematol ; 90(2): 89-98, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23181448

RESUMO

Apart from indolent systemic mastocytosis (SM), which is associated with a favorable prognosis, other subtypes of SM (SM with associated clonal hematologic non-mast cell lineage disease, aggressive SM, and mast cell leukemia - collectively referred to in this review as advanced SM) can be debilitating. The complexity of SM makes both the diagnosis and design of response criteria challenging for clinical studies. The tyrosine kinase KIT has been shown to play a crucial role in the pathogenesis of SM and has been a focal point in the development of targeted therapy. Mutations within various domains of the KIT receptor that lead to constitutive activation have been identified in patients, and those involving the activation loop of the KIT receptor are the mutations most frequently detected in patients with mastocytosis. Aberrant activation of the KIT receptor results in increased production of mast cells in extracutaneous organs that may lead to organ failure or early death. This review discusses the diagnosis and management of patients with advanced SM, including the relevance of KIT in this disease, potential therapies targeting this kinase, and criteria for measuring responses to these therapies.


Assuntos
Leucemia de Mastócitos/diagnóstico , Leucemia de Mastócitos/genética , Leucemia de Mastócitos/terapia , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Sistemas de Liberação de Medicamentos , Ativação Enzimática , Humanos , Leucemia de Mastócitos/enzimologia , Leucemia de Mastócitos/patologia , Mastócitos/enzimologia , Mastócitos/patologia , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-kit/metabolismo
19.
Br J Haematol ; 160(2): 216-9, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23078005

RESUMO

Mastocytosis is a rare disease with reported high interleukin-6 (IL6) levels influencing disease severity. The present study investigated polymorphisms within the genes that encode IL6 and its receptor (IL6R) in relation to mastocytosis development in a case-control design. Analysis of the IL6R Asp358Ala polymorphism showed that carriers of the AA genotype had a 2·5-fold lower risk for mastocytosis than those with the AC or CC genotypes. No association with mastocytosis was found for the IL6-174G/C polymorphism, however, it may influence the effect of IL6R polymorphism. To the best of our knowledge this is the first study analysing IL6/IL6R polymorphisms in mastocytosis.


Assuntos
Interleucina-6/genética , Mastocitose/genética , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina-6/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Áustria/epidemiologia , Estudos de Casos e Controles , Epistasia Genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Hungria/epidemiologia , Leucemia de Mastócitos/genética , Masculino , Mastocitose/epidemiologia , Pessoa de Meia-Idade , Polônia/epidemiologia , Adulto Jovem
20.
Pathologe ; 33(6): 539-52, 2012 Nov.
Artigo em Alemão | MEDLINE | ID: mdl-23085697

RESUMO

Mastocytosis and myeloid eosinophilic neoplasms are rare diseases of the bone marrow and are often a diagnostic challenge for hematopathologists. In mastocytosis, compact mast cell infiltrates represent the main diagnostic criterion and for myeloid eosinophilic neoplasms, eosinophilic granulocytes dominate the histological picture. Both disease groups include phenotypically and prognostically very different entities which are each defined by WHO criteria. For systemic mastocytosis (SM), a differentiation between indolent and aggressive or even leukemic forms is of prognostic importance. In indolent variants of SM, a local and/or systemic, usually reactive increase in eosinophilic granulocytes (SM-eo) is often observed. In contrast, an increase in neoplastic eosinophils is often observed in advanced SM, predominantly in diseases designated SM with associated non-mastocytic hematological neoplasms (SM-AHNMD), e.g. in SM with chronic eosinophilic leukemia (SM-CEL). Apart from mastocytoses, immunophenotypically aberrant tissue mast cells are only observed in certain rare forms of myeloid neoplasms with eosinophilia, in particular in myeloproliferative neoplasms (MPN-eo) with cytogenic anomalies in the platelet-derived growth factor receptor (PDGFR). The World Health Organization (WHO) classification of eosinophilic leukemias, however, fulfils the morphological and clinical requirements in a limited way only and needs an update.


Assuntos
Síndrome Hipereosinofílica/classificação , Síndrome Hipereosinofílica/diagnóstico , Mastocitose Sistêmica/classificação , Mastocitose Sistêmica/diagnóstico , Mastocitose/classificação , Mastocitose/diagnóstico , Biópsia por Agulha , Medula Óssea/patologia , Coristoma/patologia , Análise Citogenética , Diagnóstico Diferencial , Eosinófilos/patologia , Síndrome Hipereosinofílica/genética , Síndrome Hipereosinofílica/patologia , Imunofenotipagem , Leucemia de Mastócitos/classificação , Leucemia de Mastócitos/diagnóstico , Leucemia de Mastócitos/genética , Leucemia de Mastócitos/patologia , Mastócitos/patologia , Mastocitose/genética , Mastocitose/patologia , Mastocitose Sistêmica/genética , Mastocitose Sistêmica/patologia , Doenças Mieloproliferativas-Mielodisplásicas/classificação , Doenças Mieloproliferativas-Mielodisplásicas/diagnóstico , Doenças Mieloproliferativas-Mielodisplásicas/genética , Doenças Mieloproliferativas-Mielodisplásicas/patologia , Prognóstico , Receptores do Fator de Crescimento Derivado de Plaquetas/genética
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