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1.
Leukemia ; 34(1): 100-114, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31197259

RESUMO

Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in Toll-like receptor (TLR) signal transduction and innate immune responses. Recruitment and subsequent activation of IRAK4 upon TLR stimulation is mediated by the myeloid differentiation primary response 88 (MYD88) adaptor protein. Around 3% of chronic lymphocytic leukemia (CLL) patients have activating mutations of MYD88, a driver mutation in this disease. Here, we studied the effects of TLR activation and the pharmacological inhibition of IRAK4 with ND2158, an IRAK4 competitive inhibitor, as a therapeutic approach in CLL. Our in vitro studies demonstrated that ND2158 preferentially killed CLL cells in a dose-dependent manner. We further observed a decrease in NF-κB and STAT3 signaling, cytokine secretion, proliferation and migration of primary CLL cells from MYD88-mutated and -unmutated cases. In the Eµ-TCL1 adoptive transfer mouse model of CLL, ND2158 delayed tumor progression and modulated the activity of myeloid and T cells. Our findings show the importance of TLR signaling in CLL development and suggest IRAK4 as a therapeutic target for this disease.

2.
Br J Haematol ; 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31724172

RESUMO

Chronic lymphocytic leukaemia (CLL) is associated with alterations in T cell number, subset distribution and function. Among these changes, an increase in CD4+ T cells was reported. CD4+ T cells are a heterogeneous population and distinct subsets have been described to exert pro- and anti-tumour functions. In CLL, controversial reports describing the dominance of IFNγ-expressing Th1 T cells or of IL-4-producing Th2 T cells exist. Our study shows that blood of CLL patients is enriched in Th1 T cells producing high amounts of IFNγ. Moreover, we observed that their frequency remains relatively stable in CLL patients over a time course of five years. Furthermore, we provide evidence for an accumulation of Th1 T cells in the Eµ-TCL1 mouse model of CLL. As TBET (encoded by Tbx21) is a crucial transcription factor for Th1 polarization, we generated Tbx21-/- bone marrow chimaeric mice which showed a lower number of IFNγ-producing Th1 T cells, and used them for adoptive transfer of Eµ-TCL1 leukaemia. Disease development in these mice was, however, comparable to that in wild-type controls, excluding a major role for TBET-expressing Th1 cells in Eµ-TCL1 leukaemia. Collectively, our data highlight that Th1 T cells accumulate in CLL but reducing their number has no impact on disease development.

3.
Sci Rep ; 8(1): 10533, 2018 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-30002409

RESUMO

Apoptosis is an important physiological process in development and disease. Apoptotic cells (ACs) are a major source of self-antigens, but ACs usually evade immune responses. The mechanism by which ACs repress T cell adaptive immune responses is poorly understood. T cell activation is finely regulated by a balance of costimulatory signaling (mediated by the costimulatory receptor CD28 on T cells) and coinhibitory signaling (mediated by the coinhibitory ligands CD80 and PD-L1 and -2 on Antigen-Presenting Cells). Here, we found that ACs specifically upregulated the coinhibitory ligand CD80 on macrophages. Conversely, ACs did not exhibit a robust regulation of the other coinhibitory ligands on macrophages or the costimulatory receptor CD28 on T cells. We show that the robust positive regulation of CD80 by ACs requires phagocytosis of ACs by macrophages. We also demonstrate that CD80 modulation by dead cells is a specific effect of ACs, but not necrotic cells (which stimulate immune responses). These results indicate that ACs modulate the coinhibitory pathway of T cell activation via CD80, and suggest a role for CD80 in suppressing T cell responses by ACs. Understanding a mechanism of regulating adaptive immune responses to ACs, which harbor an abundance of self-antigens, may advance our understanding of mechanisms of regulating autoimmunity and facilitate future therapy development for autoimmune disorders.


Assuntos
Apoptose/imunologia , Autoantígenos/imunologia , Comunicação Celular/imunologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Autoantígenos/metabolismo , Autoimunidade , Antígenos B7/imunologia , Antígenos B7/metabolismo , Antígenos CD28/imunologia , Antígenos CD28/metabolismo , Linhagem Celular Tumoral , Humanos , Tolerância Imunológica/imunologia , Camundongos , Necrose/imunologia , Células RAW 264.7 , Transdução de Sinais/imunologia , Linfócitos T/metabolismo , Regulação para Cima
4.
Cancer Immunol Res ; 5(11): 1005-1015, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28947544

RESUMO

T-cell infiltration into tumors represents a critical bottleneck for immune-mediated control of cancer. We previously showed that this bottleneck can be overcome by depleting immunosuppressive Foxp3+ regulatory T cells (Tregs), a process that can increase frequencies of tumor-infiltrating lymphocytes through promoting the development of specialized portals for lymphocyte entry, namely high endothelial venules (HEVs). In this paper, we used a carcinogen-induced tumor model that allows for coevolution of the tumor microenvironment and the immune response to demonstrate that Treg depletion not only results in widespread disruption to HEV networks in lymph nodes (LNs) but also activates CD8+ T cells, which then drive intratumoral HEV development. Formation of these vessels contrasts with ontogenic HEV development in LNs in that the process is dependent on the TNF receptor and independent of lymphotoxin ß receptor-mediated signaling. These intratumoral HEVs do not express the chemokine CCL21, revealing a previously undescribed intratumoral blood vessel phenotype. We propose a model where Treg depletion enables a self-amplifying loop of T-cell activation, which promotes HEV development, T-cell infiltration, and ultimately, tumor destruction. The findings point to a need to test for HEV development as part of ongoing clinical studies in patients with cancer. Cancer Immunol Res; 5(11); 1005-15. ©2017 AACR.


Assuntos
Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Animais , Células Dendríticas/imunologia , Endotélio Vascular/imunologia , Depleção Linfocítica , Linfócitos do Interstício Tumoral/imunologia , Receptor beta de Linfotoxina/imunologia , Metilcolantreno , Camundongos , Neoplasias/induzido quimicamente , Receptores do Fator de Necrose Tumoral/imunologia
5.
Sci Immunol ; 2(13)2017 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-28754746

RESUMO

In chronic lymphocytic leukemia (CLL), monocytes and macrophages are skewed toward protumorigenic phenotypes, including the release of tumor-supportive cytokines and the expression of immunosuppressive molecules such as programmed cell death 1 ligand 1 (PD-L1). To understand the mechanism driving protumorigenic skewing in CLL, we evaluated the role of tumor cell-derived exosomes in the cross-talk with monocytes. We carried out RNA sequencing and proteome analyses of CLL-derived exosomes and identified noncoding Y RNA hY4 as a highly abundant RNA species that is enriched in exosomes from plasma of CLL patients compared with healthy donor samples. Transfer of CLL-derived exosomes or hY4 alone to monocytes resulted in key CLL-associated phenotypes, including the release of cytokines, such as C-C motif chemokine ligand 2 (CCL2), CCL4, and interleukin-6, and the expression of PD-L1. These responses were abolished in Toll-like receptor 7 (TLR7)-deficient monocytes, suggesting exosomal hY4 as a driver of TLR7 signaling. Pharmacologic inhibition of endosomal TLR signaling resulted in a substantially reduced activation of monocytes in vitro and attenuated CLL development in vivo. Our results indicate that exosome-mediated transfer of noncoding RNAs to monocytes contributes to cancer-related inflammation and concurrent immune escape via PD-L1 expression.

6.
EMBO Mol Med ; 7(8): 1034-47, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25987569

RESUMO

Metastatic breast cancer is usually diagnosed after becoming symptomatic, at which point it is rarely curable. Cell-free circulating tumor DNA (ctDNA) contains tumor-specific chromosomal rearrangements that may be interrogated in blood plasma. We evaluated serial monitoring of ctDNA for earlier detection of metastasis in a retrospective study of 20 patients diagnosed with primary breast cancer and long follow-up. Using an approach combining low-coverage whole-genome sequencing of primary tumors and quantification of tumor-specific rearrangements in plasma by droplet digital PCR, we identify for the first time that ctDNA monitoring is highly accurate for postsurgical discrimination between patients with (93%) and without (100%) eventual clinically detected recurrence. ctDNA-based detection preceded clinical detection of metastasis in 86% of patients with an average lead time of 11 months (range 0-37 months), whereas patients with long-term disease-free survival had undetectable ctDNA postoperatively. ctDNA quantity was predictive of poor survival. These findings establish the rationale for larger validation studies in early breast cancer to evaluate ctDNA as a monitoring tool for early metastasis detection, therapy modification, and to aid in avoidance of overtreatment.


Assuntos
Biomarcadores Tumorais/sangue , Neoplasias da Mama/complicações , Neoplasias da Mama/patologia , DNA/sangue , Metástase Neoplásica/diagnóstico , Feminino , Humanos , Estudos Longitudinais , Prognóstico , Estudos Retrospectivos
7.
Genome Med ; 7(1): 20, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25722745

RESUMO

BACKGROUND: Breast cancer exhibits significant molecular, pathological, and clinical heterogeneity. Current clinicopathological evaluation is imperfect for predicting outcome, which results in overtreatment for many patients, and for others, leads to death from recurrent disease. Therefore, additional criteria are needed to better personalize care and maximize treatment effectiveness and survival. METHODS: To address these challenges, the Sweden Cancerome Analysis Network - Breast (SCAN-B) consortium was initiated in 2010 as a multicenter prospective study with longsighted aims to analyze breast cancers with next-generation genomic technologies for translational research in a population-based manner and integrated with healthcare; decipher fundamental tumor biology from these analyses; utilize genomic data to develop and validate new clinically-actionable biomarker assays; and establish real-time clinical implementation of molecular diagnostic, prognostic, and predictive tests. In the first phase, we focus on molecular profiling by next-generation RNA-sequencing on the Illumina platform. RESULTS: In the first 3 years from 30 August 2010 through 31 August 2013, we have consented and enrolled 3,979 patients with primary breast cancer at the seven hospital sites in South Sweden, representing approximately 85% of eligible patients in the catchment area. Preoperative blood samples have been collected for 3,942 (99%) patients and primary tumor specimens collected for 2,929 (74%) patients. Herein we describe the study infrastructure and protocols and present initial proof of concept results from prospective RNA sequencing including tumor molecular subtyping and detection of driver gene mutations. Prospective patient enrollment is ongoing. CONCLUSIONS: We demonstrate that large-scale population-based collection and RNA-sequencing analysis of breast cancer is feasible. The SCAN-B Initiative should significantly reduce the time to discovery, validation, and clinical implementation of novel molecular diagnostic and predictive tests. We welcome the participation of additional comprehensive cancer treatment centers. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02306096.

8.
Dev Dyn ; 234(4): 1034-45, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16247769

RESUMO

Different causes, such as maternal diabetes, cloning by nuclear transfer, interspecific hybridization, and deletion of some genes such as Esx1, Ipl, or Cdkn1c, may underlie placental overgrowth. In a previous study, we carried out comparative gene expression analysis in three models of placental hyperplasias, cloning, interspecies hybridization (IHPD), and Esx1 deletion. This study identified a large number of genes that exhibited differential expression between normal and enlarged placentas; however, it remained unclear how altered expression of any specific gene was related to any specific placental phenotype. In the present study, we focused on two genes, Car2 and Ncam1, which both exhibited increased expression in interspecies and cloned hyperplastic placentas. Apart from a detailed expression analysis of both genes during normal murine placentation, we also assessed morphology of placentas that were null for Car2 or Ncam1. Finally, we attempted to rescue placental hyperplasia in a congenic model of IHPD by decreasing transcript levels of Car2 or Ncam1. In situ analysis showed that both genes are expressed mainly in the spongiotrophoblast, however, expression patterns exhibited significant variability during development. Contrary to expectations, homozygous deletion of either Car2 or Ncam1 did not result in placental phenotypes. However, expression analysis of Car3 and Ncam2, which can take over the function of Car2 and Ncam1, respectively, indicated a possible rescue mechanism, as Car3 and Ncam2 were expressed in spongiotrophoblast of Car2 and Ncam1 mutant placentas. On the other hand, downregulation of either Car2 or Ncam1 did not rescue any of the placental phenotypes of AT24 placentas, a congenic model for interspecies hybrid placentas. This strongly suggested that altered expression of Car2 and Ncam1 is a downstream event in placental hyperplasia.


Assuntos
Antígeno CD56/metabolismo , Anidrase Carbônica II/metabolismo , Regulação da Expressão Gênica , Fenótipo , Doenças Placentárias/genética , Animais , Antígeno CD56/genética , Anidrase Carbônica II/genética , Primers do DNA , Feminino , Hibridização In Situ , Camundongos , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Doenças Placentárias/patologia , Gravidez , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de DNA
9.
Hum Mol Genet ; 14(15): 2247-56, 2005 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-16002417

RESUMO

Rett syndrome (RTT) is a severe form of mental retardation, which is caused by spontaneous mutations in the X-linked gene MECP2. How the loss of MeCP2 function leads to RTT is currently unknown. Mice lacking the Mecp2 gene initially show normal postnatal development but later acquire neurological phenotypes, including heightened anxiety, that resemble RTT. The MECP2 gene encodes a methyl-CpG-binding protein that can act as a transcriptional repressor. Using cDNA microarrays, we found that Mecp2-null animals differentially express several genes that are induced during the stress response by glucocorticoids. Increased levels of mRNAs for serum glucocorticoid-inducible kinase 1 (Sgk) and FK506-binding protein 51 (Fkbp5) were observed before and after onset of neurological symptoms, but plasma glucocorticoid was not significantly elevated in Mecp2-null mice. MeCP2 is bound to the Fkbp5 and Sgk genes in brain and may function as a modulator of glucocorticoid-inducible gene expression. Given the known deleterious effect of glucocorticoid exposure on brain development, our data raise the possibility that disruption of MeCP2-dependent regulation of stress-responsive genes contributes to the symptoms of RTT.


Assuntos
Corticosterona/sangue , Regulação da Expressão Gênica , Proteínas Imediatamente Precoces/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Síndrome de Rett/metabolismo , Estresse Fisiológico/sangue , Proteínas de Ligação a Tacrolimo/metabolismo , Animais , Encéfalo/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Síndrome de Rett/genética , Transdução de Sinais , Regulação para Cima
10.
Dev Dyn ; 230(1): 149-64, 2004 May.
Artigo em Inglês | MEDLINE | ID: mdl-15108320

RESUMO

To obtain a deeper insight into the genes and gene networks involved in the development of placentopathies, we have assessed global gene expression in three different models of placental hyperplasia caused by interspecies hybridization (IHPD), cloning by nuclear transfer, and mutation of the Esx1 gene, respectively. Comparison of gene expression profiles of approximately 13,000 expressed sequence tags (ESTs) identified specific subsets of genes with changed expression levels in IHPD, cloned, and Esx1 mutant placentas. Of interest, only one gene of known function and one EST of unknown function were found common to all three placentopathies; however, a significant number of ESTs were common to IHPD and cloned placentas. In contrast, only one gene was shared between IHPD and Esx1 mutant, and cloned and Esx1 mutant placentas, respectively. These genes common to different abnormal placental growth genotypes are likely to be important in the occurrence of placentopathy.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio/genética , Placenta/metabolismo , Placenta/patologia , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição/genética , Animais , Northern Blotting , Núcleo Celular/metabolismo , Clonagem Molecular , DNA/metabolismo , DNA Complementar/metabolismo , Etiquetas de Sequências Expressas , Impressão Genômica , Genótipo , Hiperplasia , Processamento de Imagem Assistida por Computador , Hibridização In Situ , Camundongos , Mutação , Hibridização de Ácido Nucleico , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
11.
Cell Tissue Res ; 311(2): 227-37, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12596042

RESUMO

Bone marrow stromal cells (BMSC) have gained increased attention because of their multipotency and adult stem cell character. They have been shown to differentiate into other cell types of the mesenchymal lineage and also into non-mesenchymal cells. The exact identity of the original cells, which are isolated from bone marrow by their selective adherence to plastic, remains unknown to date. We have established and characterized mouse BMSC cultures and analyzed three independent samples by cDNA microarrays. The expression profile was compared with two previous expression studies of human BMSC and revealed a high degree of concordance between different techniques and species. To gain clues about the positional context and biology of the isolated cells within the bone marrow stroma, we searched our data for genes that encode proteins of the extracellular matrix, cell adhesion proteins, cytoskeletal proteins and cytokines/cytokine receptors. This analysis revealed a close association of BMSC with vascular cells and indicated that BMSC resemble pericytes.


Assuntos
Células da Medula Óssea/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Células Estromais/fisiologia , Animais , Sequência de Bases , Células da Medula Óssea/citologia , Moléculas de Adesão Celular/genética , Separação Celular/métodos , Células Cultivadas , Clonagem Molecular , Citocinas/genética , Proteínas do Citoesqueleto/genética , Primers do DNA , Proteínas da Matriz Extracelular/genética , Perfilação da Expressão Gênica/métodos , Camundongos , RNA/genética , RNA/isolamento & purificação , Receptores de Citocinas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Estromais/citologia
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