Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Nat Med ; 25(12): 1839-1842, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31768065

RESUMO

Histiocytoses are clonal hematopoietic disorders frequently driven by mutations mapping to the BRAF and MEK1 and MEK2 kinases. Currently, however, the developmental origins of histiocytoses in patients are not well understood, and clinically meaningful therapeutic targets outside of BRAF and MEK are undefined. In this study, we uncovered activating mutations in CSF1R and rearrangements in RET and ALK that conferred dramatic responses to selective inhibition of RET (selpercatinib) and crizotinib, respectively, in patients with histiocytosis.


Assuntos
Quinase do Linfoma Anaplásico/genética , Histiocitose/genética , Proteínas Proto-Oncogênicas c-ret/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Adolescente , Adulto , Aminopiridinas/farmacologia , Benzotiazóis/farmacologia , Criança , Pré-Escolar , Feminino , Genoma Humano , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Histiocitose/tratamento farmacológico , Histiocitose/patologia , Humanos , Lactente , Masculino , Mutação , Ácidos Picolínicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Pirróis/farmacologia , Receptores Proteína Tirosina Quinases/genética , Gêmeos Monozigóticos , Sequenciamento Completo do Exoma , Adulto Jovem
2.
Cancer Cell ; 36(2): 194-209.e9, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31408619

RESUMO

Cancer-associated mutations in genes encoding RNA splicing factors (SFs) commonly occur in leukemias, as well as in a variety of solid tumors, and confer dependence on wild-type splicing. These observations have led to clinical efforts to directly inhibit the spliceosome in patients with refractory leukemias. Here, we identify that inhibiting symmetric or asymmetric dimethylation of arginine, mediated by PRMT5 and type I protein arginine methyltransferases (PRMTs), respectively, reduces splicing fidelity and results in preferential killing of SF-mutant leukemias over wild-type counterparts. These data identify genetic subsets of cancer most likely to respond to PRMT inhibition, synergistic effects of combined PRMT5 and type I PRMT inhibition, and a mechanistic basis for the therapeutic efficacy of PRMT inhibition in cancer.

3.
Int J Obes (Lond) ; 43(12): 2370-2380, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31152154

RESUMO

BACKGROUND: Elevated circulating levels of the divergent transforming growth factor-beta (TGFb) family cytokine, growth differentiation factor 15 (GDF15), acting through its CNS receptor, glial-derived neurotrophic factor receptor alpha-like (GFRAL), can cause anorexia and weight loss leading to anorexia/cachexia syndrome of cancer and other diseases. Preclinical studies suggest that administration of drugs based on recombinant GDF15 might be used to treat severe obesity. However, the role of the GDF15-GFRAL pathway in the physiological regulation of body weight and metabolism is unclear. The critical site of action of GFRAL in the CNS has also not been proven beyond doubt. To investigate these two aspects, we have inhibited the actions of GDF15 in mice started on high-fat diet (HFD). METHODS: The actions of GDF15 were inhibited using two methods: (1) Groups of 8 mice under HFD had their endogenous GDF15 neutralised by monoclonal antibody treatment, (2) Groups of 15 mice received AAV-shRNA to knockdown GFRAL at its hypothesised major sites of action, the hindbrain area postrema (AP) and the nucleus of the solitary tract (NTS). Metabolic measurements were determined during both experiments. CONCLUSIONS: Treating mice with monoclonal antibody to GDF15 shortly after commencing HFD results in more rapid gain of body weight, adiposity and hepatic lipid deposition than the control groups. This is accompanied by reduced glucose and insulin tolerance and greater expression of pro-inflammatory cytokines in adipose tissue. Localised AP and NTS shRNA-GFRAL knockdown in mice commencing HFD similarly caused an increase in body weight and adiposity. This effect was in proportion to the effectiveness of GFRAL knockdown, indicated by quantitative analysis of hindbrain GFRAL staining. We conclude that the GDF15-GFRAL axis plays an important role in resistance to obesity in HFD-fed mice and that the major site of action of GDF15 in the CNS is GFRAL-expressing neurons in the AP and NTS.

4.
Nature ; 567(7749): 521-524, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30867592

RESUMO

Histiocytic neoplasms are a heterogeneous group of clonal haematopoietic disorders that are marked by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway1,2. For the 50% of patients with histiocytosis who have BRAFV600 mutations3-5, RAF inhibition is highly efficacious and has markedly altered the natural history of the disease6,7. However, no standard therapy exists for the remaining 50% of patients who lack BRAFV600 mutations. Although ERK dependence has been hypothesized to be a consistent feature across histiocytic neoplasms, this remains clinically unproven and many of the kinase mutations that are found in patients who lack BRAFV600 mutations have not previously been biologically characterized. Here we show ERK dependency in histiocytoses through a proof-of-concept clinical trial of cobimetinib, an oral inhibitor of MEK1 and MEK2, in patients with histiocytoses. Patients were enrolled regardless of their tumour genotype. In parallel, MAPK alterations that were identified in treated patients were characterized for their ability to activate ERK. In the 18 patients that we treated, the overall response rate was 89% (90% confidence interval of 73-100). Responses were durable, with no acquired resistance to date. At one year, 100% of responses were ongoing and 94% of patients remained progression-free. Cobimetinib treatment was efficacious regardless of genotype, and responses were observed in patients with ARAF, BRAF, RAF1, NRAS, KRAS, MEK1 (also known as MAP2K1) and MEK2 (also known as MAP2K2) mutations. Consistent with the observed responses, the characterization of the mutations that we identified in these patients confirmed that the MAPK-pathway mutations were activating. Collectively, these data demonstrate that histiocytic neoplasms are characterized by a notable dependence on MAPK signalling-and that they are consequently responsive to MEK inhibition. These results extend the benefits of molecularly targeted therapy to the entire spectrum of patients with histiocytosis.


Assuntos
Azetidinas/uso terapêutico , Transtornos Histiocíticos Malignos/tratamento farmacológico , Transtornos Histiocíticos Malignos/enzimologia , Histiocitose/tratamento farmacológico , Histiocitose/enzimologia , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Piperidinas/uso terapêutico , Azetidinas/farmacologia , Transtornos Histiocíticos Malignos/genética , Transtornos Histiocíticos Malignos/patologia , Histiocitose/genética , Histiocitose/patologia , Humanos , MAP Quinase Quinase 1/antagonistas & inibidores , MAP Quinase Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 2/genética , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mutação , Piperidinas/farmacologia , Intervalo Livre de Progressão , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-raf/genética
5.
Cancer Cell ; 35(3): 369-384.e7, 2019 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-30799057

RESUMO

RNA-binding proteins (RBPs) are essential modulators of transcription and translation frequently dysregulated in cancer. We systematically interrogated RBP dependencies in human cancers using a comprehensive CRISPR/Cas9 domain-focused screen targeting RNA-binding domains of 490 classical RBPs. This uncovered a network of physically interacting RBPs upregulated in acute myeloid leukemia (AML) and crucial for maintaining RNA splicing and AML survival. Genetic or pharmacologic targeting of one key member of this network, RBM39, repressed cassette exon inclusion and promoted intron retention within mRNAs encoding HOXA9 targets as well as in other RBPs preferentially required in AML. The effects of RBM39 loss on splicing further resulted in preferential lethality of spliceosomal mutant AML, providing a strategy for treatment of AML bearing RBP splicing mutations.


Assuntos
Redes Reguladoras de Genes , Marcação de Genes/métodos , Leucemia Mieloide Aguda/patologia , Proteômica/métodos , Proteínas de Ligação a RNA/genética , Regulação para Cima , Processamento Alternativo , Animais , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Células HL-60 , Proteínas de Homeodomínio/genética , Humanos , Células Jurkat , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Masculino , Camundongos , Transplante de Neoplasias , Prognóstico , Proteínas de Ligação a RNA/metabolismo , Análise de Sequência de RNA/métodos , Análise de Sobrevida
6.
Cancer Cell ; 34(2): 225-241.e8, 2018 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-30107174

RESUMO

Mutations affecting RNA splicing factors are the most common genetic alterations in myelodysplastic syndrome (MDS) patients and occur in a mutually exclusive manner. The basis for the mutual exclusivity of these mutations and how they contribute to MDS is not well understood. Here we report that although different spliceosome gene mutations impart distinct effects on splicing, they are negatively selected for when co-expressed due to aberrant splicing and downregulation of regulators of hematopoietic stem cell survival and quiescence. In addition to this synthetic lethal interaction, mutations in the splicing factors SF3B1 and SRSF2 share convergent effects on aberrant splicing of mRNAs that promote nuclear factor κB signaling. These data identify shared consequences of splicing-factor mutations and the basis for their mutual exclusivity.


Assuntos
Mutação , Neoplasias/genética , Spliceossomos , Animais , Caspase 8/genética , Feminino , Hematopoese , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/fisiologia , Fosfoproteínas/genética , Fatores de Processamento de RNA/genética , Fatores de Processamento de Serina-Arginina/genética
7.
PLoS One ; 10(7): e0133362, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26207898

RESUMO

The TGF-b superfamily cytokine MIC-1/GDF15 circulates in the blood of healthy humans. Its levels rise substantially in cancer and other diseases and this may sometimes lead to development of an anorexia/cachexia syndrome. This is mediated by a direct action of MIC-1/GDF15 on feeding centres in the hypothalamus and brainstem. More recent studies in germline gene deleted mice also suggest that this cytokine may play a role in physiological regulation of energy homeostasis. To further characterize the role of MIC-1/GDF15 in physiological regulation of energy homeostasis in man, we have examined diurnal and food associated variation in serum levels and whether variation in circulating levels relate to BMI in human monozygotic twin pairs. We found that the within twin pair differences in serum MIC-1/GDF15 levels were significantly correlated with within twin pair differences in BMI, suggesting a role for MIC-1/GDF15 in the regulation of energy balance in man. MIC-1/GDF15 serum levels altered slightly in response to a meal, but comparison with variation its serum levels over a 24 hour period suggested that these changes are likely to be due to bimodal diurnal variation which can alter serum MIC-1/GDF15 levels by about plus or minus 10% from the mesor. The lack of a rapid and substantial postprandial increase in MIC-1/GDF15 serum levels suggests that MIC1/GDF15 is unlikely to act as a satiety factor. Taken together, our findings suggest that MIC-1/GDF15 may be a physiological regulator of energy homeostasis in man, most probably due to actions on long-term regulation of energy homeostasis.


Assuntos
Índice de Massa Corporal , Ritmo Circadiano/fisiologia , Fator 15 de Diferenciação de Crescimento/sangue , Período Pós-Prandial/fisiologia , Saciação/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Colecistocinina/farmacologia , Ritmo Circadiano/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Feminino , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Saciação/efeitos dos fármacos , Gêmeos , Adulto Jovem
8.
PLoS One ; 9(6): e100370, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24971956

RESUMO

Macrophage inhibitory cytokine-1 (MIC-1/GDF15) modulates food intake and body weight under physiological and pathological conditions by acting on the hypothalamus and brainstem. When overexpressed in disease, such as in advanced cancer, elevated serum MIC-1/GDF15 levels lead to an anorexia/cachexia syndrome. To gain a better understanding of its actions in the brainstem we studied MIC-1/GDF15 induced neuronal activation identified by induction of Fos protein. Intraperitoneal injection of human MIC-1/GDF15 in mice activated brainstem neurons in the area postrema (AP) and the medial (m) portion of the nucleus of the solitary tract (NTS), which did not stain with tyrosine hydroxylase (TH). To determine the importance of these brainstem nuclei in the anorexigenic effect of MIC-1/GDF15, we ablated the AP alone or the AP and the NTS. The latter combined lesion completely reversed the anorexigenic effects of MIC-1/GDF15. Altogether, this study identified neurons in the AP and/or NTS, as being critical for the regulation of food intake and body weight by MIC-1/GDF15.


Assuntos
Depressores do Apetite/farmacologia , Área Postrema/efeitos dos fármacos , Área Postrema/fisiologia , Fator 15 de Diferenciação de Crescimento/farmacologia , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/fisiologia , Animais , Anorexia/induzido quimicamente , Depressores do Apetite/administração & dosagem , Fator 15 de Diferenciação de Crescimento/administração & dosagem , Infusões Intraventriculares , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Perda de Peso/efeitos dos fármacos
9.
PLoS One ; 8(2): e55174, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23468844

RESUMO

The TGF-b superfamily cytokine MIC-1/GDF15 circulates in all humans and when overproduced in cancer leads to anorexia/cachexia, by direct action on brain feeding centres. In these studies we have examined the role of physiologically relevant levels of MIC-1/GDF15 in the regulation of appetite, body weight and basal metabolic rate. MIC-1/GDF15 gene knockout mice (MIC-1(-/-)) weighed more and had increased adiposity, which was associated with increased spontaneous food intake. Female MIC-1(-/-) mice exhibited some additional alterations in reduced basal energy expenditure and physical activity, possibly owing to the associated decrease in total lean mass. Further, infusion of human recombinant MIC-1/GDF15 sufficient to raise serum levels in MIC-1(-/-) mice to within the normal human range reduced body weight and food intake. Taken together, our findings suggest that MIC-1/GDF15 is involved in the physiological regulation of appetite and energy storage.


Assuntos
Apetite/genética , Peso Corporal/genética , Fator 15 de Diferenciação de Crescimento/genética , Tecido Adiposo/crescimento & desenvolvimento , Animais , Apetite/fisiologia , Peso Corporal/fisiologia , Ingestão de Alimentos , Metabolismo Energético/genética , Feminino , Genótipo , Fator 15 de Diferenciação de Crescimento/metabolismo , Humanos , Masculino , Camundongos , Camundongos Knockout , Tamanho do Órgão , Fatores Sexuais , Transdução de Sinais , Ganho de Peso/genética
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA