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1.
Nature ; 546(7657): 302-306, 2017 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-28562582

RESUMO

Similar to resting mature B cells, where the B-cell antigen receptor (BCR) controls cellular survival, surface BCR expression is conserved in most mature B-cell lymphomas. The identification of activating BCR mutations and the growth disadvantage upon BCR knockdown of cells of certain lymphoma entities has led to the view that BCR signalling is required for tumour cell survival. Consequently, the BCR signalling machinery has become an established target in the therapy of B-cell malignancies. Here we study the effects of BCR ablation on MYC-driven mouse B-cell lymphomas and compare them with observations in human Burkitt lymphoma. Whereas BCR ablation does not, per se, significantly affect lymphoma growth, BCR-negative (BCR-) tumour cells rapidly disappear in the presence of their BCR-expressing (BCR+) counterparts in vitro and in vivo. This requires neither cellular contact nor factors released by BCR+ tumour cells. Instead, BCR loss induces the rewiring of central carbon metabolism, increasing the sensitivity of receptor-less lymphoma cells to nutrient restriction. The BCR attenuates glycogen synthase kinase 3 beta (GSK3ß) activity to support MYC-controlled gene expression. BCR- tumour cells exhibit increased GSK3ß activity and are rescued from their competitive growth disadvantage by GSK3ß inhibition. BCR- lymphoma variants that restore competitive fitness normalize GSK3ß activity after constitutive activation of the MAPK pathway, commonly through Ras mutations. Similarly, in Burkitt lymphoma, activating RAS mutations may propagate immunoglobulin-crippled tumour cells, which usually represent a minority of the tumour bulk. Thus, while BCR expression enhances lymphoma cell fitness, BCR-targeted therapies may profit from combinations with drugs targeting BCR- tumour cells.


Assuntos
Linfócitos B/metabolismo , Genes myc , Aptidão Genética , Glicogênio Sintase Quinase 3 beta/antagonistas & inibidores , Linfoma/genética , Linfoma/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Animais , Linfócitos B/imunologia , Linfócitos B/patologia , Linfoma de Burkitt/genética , Linfoma de Burkitt/imunologia , Linfoma de Burkitt/patologia , Carbono/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Genes ras/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Linfoma/enzimologia , Linfoma/patologia , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Mutação , Receptores de Antígenos de Linfócitos B/deficiência , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/imunologia , Células Tumorais Cultivadas
2.
Front Immunol ; 10: 1640, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31396210

RESUMO

Altered macrophage infiltration upon tissue damage results in inadequate healing due to inappropriate remodeling and stem cell recruitment and differentiation. We investigated in vivo whether cells of endothelial origin phenotypically change upon heterotopic ossification induction and whether infiltration of innate immunity cells influences their commitment and alters the ectopic bone formation. Liposome-encapsulated clodronate was used to assess macrophage impact on endothelial cells in the skeletal muscle upon acute damage in the ECs specific lineage-tracing Cdh5CreERT2:R26REYFP/dtTomato transgenic mice. Macrophage depletion in the injured skeletal muscle partially shifts the fate of ECs toward endochondral differentiation. Upon ectopic stimulation of BMP signaling, monocyte depletion leads to an enhanced contribution of ECs chondrogenesis and to ectopic bone formation, with increased bone volume and density, that is reversed by ACVR1/SMAD pathway inhibitor dipyridamole. This suggests that macrophages contribute to preserve endothelial fate and to limit the bone lesion in a BMP/injury-induced mouse model of heterotopic ossification. Therefore, alterations of the macrophage-endothelial axis may represent a novel target for molecular intervention in heterotopic ossification.


Assuntos
Condrogênese , Células Endoteliais/fisiologia , Macrófagos/imunologia , Monócitos/imunologia , Músculo Esquelético/patologia , Ossificação Heterotópica/imunologia , Animais , Camundongos Transgênicos , Músculo Esquelético/fisiologia
3.
Dis Model Mech ; 9(6): 685-96, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27125279

RESUMO

The ACVR1 gene encodes a type I receptor of bone morphogenetic proteins (BMPs). Activating mutations in ACVR1 are responsible for fibrodysplasia ossificans progressiva (FOP), a rare disease characterized by congenital toe malformation and progressive heterotopic endochondral ossification leading to severe and cumulative disability. Until now, no therapy has been available to prevent soft-tissue swelling (flare-ups) that trigger the ossification process. With the aim of finding a new therapeutic strategy for FOP, we developed a high-throughput screening (HTS) assay to identify inhibitors of ACVR1 gene expression among drugs already approved for the therapy of other diseases. The screening, based on an ACVR1 promoter assay, was followed by an in vitro and in vivo test to validate and characterize candidate molecules. Among compounds that modulate the ACVR1 promoter activity, we selected the one showing the highest inhibitory effect, dipyridamole, a drug that is currently used as a platelet anti-aggregant. The inhibitory effect was detectable on ACVR1 gene expression, on the whole Smad-dependent BMP signaling pathway, and on chondrogenic and osteogenic differentiation processes by in vitro cellular assays. Moreover, dipyridamole reduced the process of heterotopic bone formation in vivo Our drug repositioning strategy has led to the identification of dipyridamole as a possible therapeutic tool for the treatment of FOP. Furthermore, our study has also defined a pipeline of assays that will be useful for the evaluation of other pharmacological inhibitors of heterotopic ossification.


Assuntos
Receptores de Ativinas Tipo I/genética , Ensaios de Triagem em Larga Escala/métodos , Miosite Ossificante/tratamento farmacológico , Transcrição Gênica , Animais , Biomarcadores/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Cálcio/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Condrogênese/efeitos dos fármacos , Dipiridamol/farmacologia , Dipiridamol/uso terapêutico , Modelos Animais de Doenças , Camundongos , Miosite Ossificante/metabolismo , Miosite Ossificante/patologia , Ossificação Heterotópica/diagnóstico por imagem , Ossificação Heterotópica/patologia , Osteoblastos/citologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteogênese/efeitos dos fármacos , Reprodutibilidade dos Testes , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Transcrição Gênica/efeitos dos fármacos
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