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2.
Nat Commun ; 10(1): 2235, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138805

RESUMO

Pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors in desperate need of a curative treatment. Oncolytic virotherapy is emerging as a solid therapeutic approach. Delta-24-RGD is a replication competent adenovirus engineered to replicate in tumor cells with an aberrant RB pathway. This virus has proven to be safe and effective in adult gliomas. Here we report that the administration of Delta-24-RGD is safe in mice and results in a significant increase in survival in immunodeficient and immunocompetent models of pHGG and DIPGs. Our results show that the Delta-24-RGD antiglioma effect is mediated by the oncolytic effect and the immune response elicited against the tumor. Altogether, our data highlight the potential of this virus as treatment for patients with these tumors. Of clinical significance, these data have led to the start of a phase I/II clinical trial at our institution for newly diagnosed DIPG (NCT03178032).


Assuntos
Adenoviridae , Neoplasias do Tronco Encefálico/terapia , Glioma/terapia , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos , Animais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Neoplasias do Tronco Encefálico/patologia , Linhagem Celular Tumoral , Sobrevivência Celular , Simulação por Computador , Modelos Animais de Doenças , Glioma/patologia , Humanos , Técnicas In Vitro , Camundongos , Gradação de Tumores , Ensaios Antitumorais Modelo de Xenoenxerto
3.
J Pathol ; 245(1): 61-73, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29464716

RESUMO

The increased risk of Richter transformation (RT) in patients with chronic lymphocytic leukaemia (CLL) due to Epstein-Barr virus (EBV) reactivation during immunosuppressive therapy with fludarabine other targeted agents remains controversial. Among 31 RT cases classified as diffuse large B-cell lymphoma (DLBCL), seven (23%) showed EBV expression. In contrast to EBV- tumours, EBV+ DLBCLs derived predominantly from IGVH-hypermutated CLL, and they also showed CLL-unrelated IGVH sequences more frequently. Intriguingly, despite having different cellular origins, clonally related and unrelated EBV+ DLBCLs shared a previous history of immunosuppressive chemo-immunotherapy, a non-germinal centre DLBCL phenotype, EBV latency programme type II or III, and very short survival. These data suggested that EBV reactivation during therapy-related immunosuppression can transform either CLL cells or non-tumoural B lymphocytes into EBV+ DLBCL. To investigate this hypothesis, xenogeneic transplantation of blood cells from 31 patients with CLL and monoclonal B-cell lymphocytosis (MBL) was performed in Rag2-/- IL2γc-/- mice. Remarkably, the recipients' impaired immunosurveillance favoured the spontaneous outgrowth of EBV+ B-cell clones from 95% of CLL and 64% of MBL patients samples, but not from healthy donors. Eventually, these cells generated monoclonal tumours (mostly CLL-unrelated but also CLL-related), recapitulating the principal features of EBV+ DLBCL in patients. Accordingly, clonally related and unrelated EBV+ DLBCL xenografts showed indistinguishable cellular, virological and molecular features, and synergistically responded to combined inhibition of EBV replication with ganciclovir and B-cell receptor signalling with ibrutinib in vivo. Our study underscores the risk of RT driven by EBV in CLL patients receiving immunosuppressive therapies, and provides the scientific rationale for testing ganciclovir and ibrutinib in EBV+ DLBCL. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Transformação Celular Neoplásica/efeitos dos fármacos , Herpesvirus Humano 4/efeitos dos fármacos , Imunossupressores/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Adulto , Idoso , Linfócitos B/efeitos dos fármacos , Linfócitos B/patologia , Transformação Celular Neoplásica/patologia , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/patologia , Feminino , Herpesvirus Humano 4/genética , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Masculino , Pessoa de Meia-Idade
5.
Nat Commun ; 7: 11889, 2016 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-27297662

RESUMO

NKX2 homeobox family proteins have a role in cancer development. Here we show that NKX2-3 is overexpressed in tumour cells from a subset of patients with marginal-zone lymphomas, but not with other B-cell malignancies. While Nkx2-3-deficient mice exhibit the absence of marginal-zone B cells, transgenic mice with expression of NKX2-3 in B cells show marginal-zone expansion that leads to the development of tumours, faithfully recapitulating the principal clinical and biological features of human marginal-zone lymphomas. NKX2-3 induces B-cell receptor signalling by phosphorylating Lyn/Syk kinases, which in turn activate multiple integrins (LFA-1, VLA-4), adhesion molecules (ICAM-1, MadCAM-1) and the chemokine receptor CXCR4. These molecules enhance migration, polarization and homing of B cells to splenic and extranodal tissues, eventually driving malignant transformation through triggering NF-κB and PI3K-AKT pathways. This study implicates oncogenic NKX2-3 in lymphomagenesis, and provides a valid experimental mouse model for studying the biology and therapy of human marginal-zone B-cell lymphomas.


Assuntos
Proteínas de Homeodomínio/genética , Linfócitos/metabolismo , Linfoma de Zona Marginal Tipo Células B/genética , Receptores de Antígenos de Linfócitos B/genética , Transdução de Sinais/genética , Fatores de Transcrição/genética , Animais , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Perfilação da Expressão Gênica , Proteínas de Homeodomínio/metabolismo , Humanos , Estimativa de Kaplan-Meier , Tecido Linfoide/metabolismo , Linfoma de Zona Marginal Tipo Células B/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Receptores de Antígenos de Linfócitos B/metabolismo , Quinase Syk/genética , Quinase Syk/metabolismo , Fatores de Transcrição/metabolismo
6.
Int Rev Immunol ; 35(6): 489-502, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26186200

RESUMO

Despite their functional similarities, peripheral lymphoid tissues are remarkably different according to their developmental properties and structural characteristics, including their specified vasculature. Access of leukocytes to these organs critically depends on their interactions with the local endothelium, where endothelial cells are patterned to display a restricted set of adhesion molecules and other regulatory compounds necessary for extravasation. Recent advances in high throughput analyses of highly purified endothelial subsets in various lymphoid tissues as well as the expansion of various transgenic animal models have shed new light on the transcriptional complexities of lymphoid tissue vascular endothelium. This review is aimed at providing a comprehensive analysis linking the functional competence of spleen and intestinal lymphoid tissues with the developmental programming and functional divergence of their vascular specification, with particular emphasis on the transcriptional control of endothelial cells exerted by Nkx2.3 homeodomain transcription factor.


Assuntos
Diferenciação Celular/imunologia , Células Endoteliais/fisiologia , Endotélio Vascular/fisiologia , Regulação da Expressão Gênica/imunologia , Tecido Linfoide/irrigação sanguínea , Tecido Linfoide/fisiologia , Animais , Animais Geneticamente Modificados , Endotélio Vascular/citologia , Sequenciamento de Nucleotídeos em Larga Escala , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/imunologia , Humanos , Intestinos/irrigação sanguínea , Intestinos/embriologia , Intestinos/fisiologia , Leucócitos/imunologia , Tecido Linfoide/embriologia , Camundongos , Organogênese , Nódulos Linfáticos Agregados/irrigação sanguínea , Nódulos Linfáticos Agregados/embriologia , Nódulos Linfáticos Agregados/fisiologia , Análise de Sequência de RNA , Baço/irrigação sanguínea , Baço/embriologia , Baço/fisiologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia
7.
BMC Genomics ; 16: 752, 2015 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-26444668

RESUMO

BACKGROUND: The development of a more refined prognostic methodology for early non-small cell lung cancer (NSCLC) is an unmet clinical need. An accurate prognostic tool might help to select patients at early stages for adjuvant therapies. RESULTS: A new integrated bioinformatics searching strategy, that combines gene copy number alterations and expression, together with clinical parameters was applied to derive two prognostic genomic signatures. The proposed methodology combines data from patients with and without clinical data with a priori information on the ability of a gene to be a prognostic marker. Two initial candidate sets of 513 and 150 genes for lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC), respectively, were generated by identifying genes which have both: a) significant correlation between copy number and gene expression, and b) significant prognostic value at the gene expression level in external databases. From these candidates, two panels of 7 (ADC) and 5 (SCC) genes were further identified via semi-supervised learning. These panels, together with clinical data (stage, age and sex), were used to construct the ADC and SCC hazard scores combining clinical and genomic data. The signatures were validated in two independent datasets (n = 73 for ADC, n = 97 for SCC), confirming that the prognostic value of both clinical-genomic models is robust, statistically significant (P = 0.008 for ADC and P = 0.019 for SCC) and outperforms both the clinical models (P = 0.060 for ADC and P = 0.121 for SCC) and the genomic models applied separately (P = 0.350 for ADC and P = 0.269 for SCC). CONCLUSION: The present work provides a methodology to generate a robust signature using copy number data that can be potentially used to any cancer. Using it, we found new prognostic scores based on tumor DNA that, jointly with clinical information, are able to predict overall survival (OS) in patients with early-stage ADC and SCC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Dosagem de Genes/genética , Proteínas de Neoplasias/genética , Prognóstico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Feminino , Regulação Neoplásica da Expressão Gênica , Genoma Humano , Genômica , Humanos , Estimativa de Kaplan-Meier , Masculino , Proteínas de Neoplasias/biossíntese , Estadiamento de Neoplasias
8.
Blood ; 125(12): 1922-31, 2015 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-25612624

RESUMO

Splenic marginal zone lymphoma is a rare lymphoma. Loss of 7q31 and somatic mutations affecting the NOTCH2 and KLF2 genes are the commonest genomic aberrations. Epigenetic changes can be pharmacologically reverted; therefore, identification of groups of patients with specific epigenomic alterations might have therapeutic relevance. Here we integrated genome-wide DNA-promoter methylation profiling with gene expression profiling, and clinical and biological variables. An unsupervised clustering analysis of a test series of 98 samples identified 2 clusters with different degrees of promoter methylation. The cluster comprising samples with higher-promoter methylation (High-M) had a poorer overall survival compared with the lower (Low-M) cluster. The prognostic relevance of the High-M phenotype was confirmed in an independent validation set of 36 patients. In the whole series, the High-M phenotype was associated with IGHV1-02 usage, mutations of NOTCH2 gene, 7q31-32 loss, and histologic transformation. In the High-M set, a number of tumor-suppressor genes were methylated and repressed. PRC2 subunit genes and several prosurvival lymphoma genes were unmethylated and overexpressed. A model based on the methylation of 3 genes (CACNB2, HTRA1, KLF4) identified a poorer-outcome patient subset. Exposure of splenic marginal zone lymphoma cell lines to a demethylating agent caused partial reversion of the High-M phenotype and inhibition of proliferation.


Assuntos
Metilação de DNA , Linfoma de Zona Marginal Tipo Células B/genética , Neoplasias Esplênicas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células , Transformação Celular Neoplásica , Análise por Conglomerados , Análise Mutacional de DNA , Feminino , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Prognóstico , Regiões Promotoras Genéticas , Neoplasias Esplênicas/diagnóstico , Neoplasias Esplênicas/mortalidade , Resultado do Tratamento
9.
Blood ; 123(26): 4111-9, 2014 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-24786774

RESUMO

Acquired resistance to targeted drugs is emerging as an obstacle to successful cancer treatment. Recently, a BCL2-selective BH3 mimetic termed ABT-199 showed promising therapeutic results in BCL2-dependent tumors. Based on its high affinity for BCL2, we studied potential mechanisms conferring resistance upon ABT-199 therapy, aiming to anticipate its occurrence in the clinic. Two models of resistant lymphomas were established by continuous ABT-199 exposure. In resistant Bcl2-expressing mouse lymphoma cells, 2 missense mutations within the Bcl2 BH3 domain were identified. Both F101C and F101L mutations impeded ABT-199 binding to the BH3 domain, therefore suppressing mitochondrial apoptosis. In resistant human lymphoma cells, a missense mutation in the C-terminal transmembrane domain of proapoptotic BAX (G179E) was found, which abrogated BAX anchoring to mitochondria and blocked ABT-199-induced apoptosis both in vitro and in vivo. Importantly, G179E BAX mutation also induced partial cross-resistance to other antineoplastic drugs. Our study reveals the acquisition of mutations in BCL2 family proteins as a novel mechanism of apoptosis resistance in cancer. These results anticipate the potential development of such mutations in patients treated with ABT-199, providing a basis to preventing their occurrence and to designing drugs able to circumvent the acquired resistance.


Assuntos
Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linfoma/metabolismo , Mutação de Sentido Incorreto , Sulfonamidas/farmacologia , Proteína X Associada a bcl-2/metabolismo , Substituição de Aminoácidos , Animais , Antineoplásicos , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Linfoma/tratamento farmacológico , Linfoma/genética , Linfoma/patologia , Camundongos , Camundongos Knockout , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteína X Associada a bcl-2/genética
10.
Curr Opin Hematol ; 21(4): 309-19, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24867288

RESUMO

PURPOSE OF REVIEW: Extranodal mucosa-associated lymphoid tissue (MALT lymphoma) is a distinct clinical-pathological entity that can be distinguished from other lymphomas by a number of unique features, including their location in various extranodal sites, being preceded by chronic inflammatory or infection processes; a characteristic histopathological picture; and the presence of exclusive chromosomal translocations which increase MALT1 proteolytic activity to promote constitutive NF-κB signaling and eventually drive lymphomagenesis. RECENT FINDINGS: This review explores the major molecular and cellular events that participate in MALT lymphoma pathogenesis, focusing on gastric MALT lymphoma as a model of chronic inflammation-induced tumor development. In addition, the pivotal roles of activated MALT1 protease, its substrate TNFAIP3/A20, and the MyD88 adaptor protein in abnormally triggering downstream NF-κB pathway are overviewed. These new insights provide a mechanistic basis for using novel therapies targeting MALT1 protease or IRAK4 kinase activities. Finally, the putative cellular origin of MALT lymphomas is also discussed. SUMMARY: Over the last decade, unraveling the biological complexity of MALT lymphomas has shed light on the fundamental cellular and molecular aspects of the disease that are to be translated into clinical diagnostics and therapy.


Assuntos
Linfoma de Zona Marginal Tipo Células B/etiologia , Animais , Caspases/genética , Doença Crônica , Humanos , Inflamação/complicações , Linfoma de Zona Marginal Tipo Células B/tratamento farmacológico , Linfoma de Zona Marginal Tipo Células B/metabolismo , Terapia de Alvo Molecular , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Mutação , NF-kappa B/metabolismo , Proteínas de Neoplasias/genética , Transdução de Sinais , Translocação Genética
11.
PLoS One ; 8(10): e77098, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24155920

RESUMO

Glioblastoma multiforme (GBM)-initiating cells (GICs) represent a tumor subpopulation with neural stem cell-like properties that is responsible for the development, progression and therapeutic resistance of human GBM. We have recently shown that blockade of NFκB pathway promotes terminal differentiation and senescence of GICs both in vitro and in vivo, indicating that induction of differentiation may be a potential therapeutic strategy for GBM. MicroRNAs have been implicated in the pathogenesis of GBM, but a high-throughput analysis of their role in GIC differentiation has not been reported. We have established human GIC cell lines that can be efficiently differentiated into cells expressing astrocytic and neuronal lineage markers. Using this in vitro system, a microarray-based high-throughput analysis to determine global expression changes of microRNAs during differentiation of GICs was performed. A number of changes in the levels of microRNAs were detected in differentiating GICs, including over-expression of hsa-miR-21, hsa-miR-29a, hsa-miR-29b, hsa-miR-221 and hsa-miR-222, and down-regulation of hsa-miR-93 and hsa-miR-106a. Functional studies showed that miR-21 over-expression in GICs induced comparable cell differentiation features and targeted SPRY1 mRNA, which encodes for a negative regulator of neural stem-cell differentiation. In addition, miR-221 and miR-222 inhibition in differentiated cells restored the expression of stem cell markers while reducing differentiation markers. Finally, miR-29a and miR-29b targeted MCL1 mRNA in GICs and increased apoptosis. Our study uncovers the microRNA dynamic expression changes occurring during differentiation of GICs, and identifies miR-21 and miR-221/222 as key regulators of this process.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Diferenciação Celular/genética , Glioblastoma/genética , Glioblastoma/patologia , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Apoptose/genética , Astrócitos/metabolismo , Astrócitos/patologia , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/cirurgia , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteína Glial Fibrilar Ácida/metabolismo , Glioblastoma/cirurgia , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Células-Tronco Neoplásicas/patologia , Nestina/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Fosfoproteínas/metabolismo , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Tubulina (Proteína)/metabolismo
12.
Br J Haematol ; 162(5): 621-30, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23795761

RESUMO

We have previously reported that LITAF is silenced by promoter hypermethylation in germinal centre-derived B-cell lymphomas, but beyond these data the regulation and function of lipopolysaccharide-induced tumour necrosis factor (TNF) factor (LITAF) in B cells are unknown. Gene expression and immunohistochemical studies revealed that LITAF and BCL6 show opposite expression in tonsil B-cell subpopulations and B-cell lymphomas, suggesting that BCL6 may regulate LITAF expression. Accordingly, BCL6 silencing increased LITAF expression, and chromatin immunoprecipitation and luciferase reporter assays demonstrated a direct transcriptional repression of LITAF by BCL6. Gain- and loss-of-function experiments in different B-cell lymphoma cell lines revealed that, in contrast to its function in monocytes, LITAF does not induce lipopolysaccharide-mediated TNF secretion in B cells. However, gene expression microarrays defined a LITAF-related transcriptional signature containing genes regulating autophagy, including MAP1LC3B (LC3B). In addition, immunofluorescence analysis co-localized LITAF with autophagosomes, further suggesting a possible role in autophagy modulation. Accordingly, ectopic LITAF expression in B-cell lymphoma cells enhanced autophagy responses to starvation, which were impaired upon LITAF silencing. Our results indicate that the BCL6-mediated transcriptional repression of LITAF may inhibit autophagy in B cells during the germinal centre reaction, and suggest that the constitutive repression of autophagy responses in BCL6-driven lymphomas may contribute to lymphomagenesis.


Assuntos
Autofagia/genética , Linfoma de Células B/genética , Proteínas de Neoplasias/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Subpopulações de Linfócitos B/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Íntrons , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6 , Fatores de Transcrição/metabolismo , Transcrição Genética , Fator de Necrose Tumoral alfa/metabolismo
13.
Cell Rep ; 3(4): 1153-63, 2013 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-23545498

RESUMO

Earlier work demonstrated that the transcription factor C/EBPα can convert immature and mature murine B lineage cells into functional macrophages. Testing >20 human lymphoma and leukemia B cell lines, we found that most can be transdifferentiated at least partially into macrophage-like cells, provided that C/EBPα is expressed at sufficiently high levels. A tamoxifen-inducible subclone of the Seraphina Burkitt lymphoma line, expressing C/EBPαER, could be efficiently converted into phagocytic and quiescent cells with a transcriptome resembling normal macrophages. The converted cells retained their phenotype even when C/EBPα was inactivated, a hallmark of cell reprogramming. Interestingly, C/EBPα induction also impaired the cells' tumorigenicity. Likewise, C/EBPα efficiently converted a lymphoblastic leukemia B cell line into macrophage-like cells, again dramatically impairing their tumorigenicity. Our experiments show that human cancer cells can be induced by C/EBPα to transdifferentiate into seemingly normal cells at high frequencies and provide a proof of principle for a potential new therapeutic strategy for treating B cell malignancies.


Assuntos
Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Macrófagos/citologia , Animais , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Hormonais/toxicidade , Linhagem Celular Tumoral , Linhagem da Célula , Transdiferenciação Celular/efeitos dos fármacos , Humanos , Leucemia/metabolismo , Leucemia/patologia , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/metabolismo , Linfoma de Células B/mortalidade , Macrófagos/metabolismo , Camundongos , Fagocitose , Tamoxifeno/uso terapêutico , Tamoxifeno/toxicidade , Transcriptoma , Transplante Heterólogo
14.
Blood ; 121(21): 4311-20, 2013 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-23580662

RESUMO

B-cell maturation and germinal center (GC) formation are dependent on the interplay between BCL6 and other transcriptional regulators. FOXP1 is a transcription factor that regulates early B-cell development, but whether it plays a role in mature B cells is unknown. Analysis of human tonsillar B-cell subpopulations revealed that FOXP1 shows the opposite expression pattern to BCL6, suggesting that FOXP1 regulates the transition from resting follicular B cell to activated GC B cell. Chromatin immunoprecipitation-on-chip and gene expression assays on B cells indicated that FOXP1 acts as a transcriptional activator and repressor of genes involved in the GC reaction, half of which are also BCL6 targets. To study FOXP1 function in vivo, we developed transgenic mice expressing human FOXP1 in lymphoid cells. These mice exhibited irregular formation of splenic GCs, showing a modest increase in naïve and marginal-zone B cells and a significant decrease in GC B cells. Furthermore, aberrant expression of FOXP1 impaired transcription of noncoding γ1 germline transcripts and inhibited efficient class switching to the immunoglobulin G1 isotype. These studies show that FOXP1 is physiologically downregulated in GC B cells and that aberrant expression of FOXP1 impairs mechanisms triggered by B-cell activation, potentially contributing to B-cell lymphomagenesis.


Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Centro Germinativo/citologia , Linfoma/imunologia , Proteínas Repressoras/metabolismo , Animais , Diferenciação Celular/imunologia , Linhagem Celular , Proteínas de Ligação a DNA/imunologia , Proteínas de Ligação a DNA/metabolismo , Regulação para Baixo/imunologia , Fatores de Transcrição Forkhead/imunologia , Centro Germinativo/imunologia , Humanos , Linfoma/metabolismo , Camundongos , Camundongos Transgênicos , Tonsila Palatina/citologia , Proteínas Proto-Oncogênicas c-bcl-6 , Proteínas Repressoras/imunologia , Ativação Transcricional/imunologia
15.
Methods Mol Biol ; 973: 147-63, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23412788

RESUMO

Genomic profiling of mantle cell lymphoma (MCL) cells has enabled a better understanding of the complex mechanisms underlying the pathogenesis of disease. Besides the t(11;14)(q13;q32) leading to cyclin D1 overexpression, MCL exhibits a characteristic pattern of DNA copy number aberrations that differs from those detected in other B-cell lymphomas. These genomic changes disrupt selected oncogenes and suppressor genes that are required for lymphoma development and progression, many of which are components of cell cycle, DNA damage response and repair, apoptosis, and cell-signaling pathways. Additionally, some of them may represent effective therapeutic targets. A number of genomic and molecular abnormalities have been correlated with the clinical outcome of patients with MCL and are considered prognostic factors. However, only a few genomic markers have been shown to predict the response to current or novel targeted therapies. One representative example is the high-level amplification of the BCL2 gene, which predicts a good response to pro-apoptotic BH3 mimetic drugs. In summary, genomic analyses have contributed to the substantial advances made in the comprehension of the pathogenesis of MCL, providing a solid basis for the identification of optimal therapeutic targets and for the design of new molecular therapies aiming to cure this fatal disease.


Assuntos
Perfilação da Expressão Gênica/métodos , Linfoma de Célula do Manto/genética , Aberrações Cromossômicas , Hibridização Genômica Comparativa/métodos , Ciclina D1/genética , Humanos , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/patologia , Linfoma de Célula do Manto/terapia , Prognóstico , Dissomia Uniparental/genética
16.
Stem Cells ; 31(6): 1075-85, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23401361

RESUMO

Glioblastoma (GBM) is associated with infiltration of peritumoral (PT) parenchyma by isolated tumor cells that leads to tumor regrowth. Recently, GBM stem-like or initiating cells (GICs) have been identified in the PT area, but whether these GICs have enhanced migratory and invasive capabilities compared with GICs from the tumor mass (TM) is presently unknown. We isolated GICs from the infiltrated PT tissue and the TM of three patients and found that PT cells have an advantage over TM cells in two-dimensional and three-dimensional migration and invasion assays. Interestingly, PT cells display a high plasticity in protrusion formation and cell shape and their migration is insensitive to substrate stiffness, which represent advantages to infiltrate microenvironments of different rigidity. Furthermore, mouse and chicken embryo xenografts revealed that only PT cells showed a dispersed distribution pattern, closely associated to blood vessels. Consistent with cellular plasticity, simultaneous Rac and RhoA activation are required for the enhanced invasive capacity of PT cells. Moreover, Rho GTPase signaling modulators αVß3 and p27 play key roles in GIC invasiveness. Of note, p27 is upregulated in TM cells and inhibits RhoA activity. Gene silencing of p27 increased the invasive capacity of TM GICs. Additionally, ß3 integrin is upregulated in PT cells. Blockade of dimeric integrin αVß3, a Rac activator, reduced the invasive capacity of PT GICs in vitro and abrogated the spreading of PT cells into chicken embryos. Thus, our results describe the invasive features acquired by a unique subpopulation of GICs that infiltrate neighboring tissue.


Assuntos
Neoplasias Encefálicas/patologia , Movimento Celular/fisiologia , Glioblastoma/patologia , Células-Tronco Neoplásicas/patologia , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Embrião de Galinha , Regulação para Baixo , Feminino , Glioblastoma/genética , Glioblastoma/metabolismo , Xenoenxertos , Humanos , Integrina alfaVbeta3/genética , Integrina alfaVbeta3/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Invasividade Neoplásica , Células-Tronco Neoplásicas/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , Regulação para Cima , Proteínas rac de Ligação ao GTP/genética , Proteínas rac de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo
17.
Nat Commun ; 4: 1338, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23299888

RESUMO

The human germinal centre-associated lymphoma gene is specifically expressed in germinal centre B-lymphocytes and germinal centre-derived B-cell lymphomas, but its function is largely unknown. Here we demonstrate that human germinal centre-associated lymphoma directly binds to Syk in B cells, increases its kinase activity on B-cell receptor stimulation and leads to enhanced activation of Syk downstream effectors. To further investigate these findings in vivo, human germinal centre-associated lymphoma transgenic mice were generated. Starting from 12 months of age these mice developed polyclonal B-cell lymphoid hyperplasia, hypergammaglobulinemia and systemic reactive amyloid A (AA) amyloidosis, leading to shortened survival. The lymphoid hyperplasia in the human germinal centre-associated lymphoma transgenic mice are likely attributable to enhanced B-cell receptor signalling as shown by increased Syk phosphorylation, ex vivo B-cell proliferation and increased RhoA activation. Overall, our study shows for the first time that the germinal centre protein human germinal centre-associated lymphoma regulates B-cell receptor signalling in B-lymphocytes which, without appropriate control, may lead to B-cell lymphoproliferation.


Assuntos
Amiloidose/patologia , Centro Germinativo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Linfoma de Células B/enzimologia , Linfoma de Células B/patologia , Proteínas de Neoplasias/metabolismo , Proteínas Tirosina Quinases/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Sequência de Aminoácidos , Amiloidose/complicações , Animais , Antígenos Ly/metabolismo , Extratos Celulares , Modelos Animais de Doenças , Ativação Enzimática , Centro Germinativo/patologia , Humanos , Hipergamaglobulinemia/patologia , Hiperplasia , Espaço Intracelular/metabolismo , Estimativa de Kaplan-Meier , Linfoma de Células B/complicações , Proteínas de Membrana/metabolismo , Camundongos , Proteínas dos Microfilamentos , Dados de Sequência Molecular , Ligação Proteica , RNA Interferente Pequeno/metabolismo , Proteína Amiloide A Sérica/química , Proteína Amiloide A Sérica/metabolismo , Transdução de Sinais , Baço/metabolismo , Baço/patologia , Quinase Syk , Transcriptoma/genética , Proteína rhoA de Ligação ao GTP/metabolismo
18.
Proc Natl Acad Sci U S A ; 109(26): 10534-9, 2012 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-22689981

RESUMO

Chromosomal translocations involving the MALT1 gene are hallmarks of mucosa-associated lymphoid tissue (MALT) lymphoma. To date, targeting these translocations to mouse B cells has failed to reproduce human disease. Here, we induced MALT1 expression in mouse Sca1(+)Lin(-) hematopoietic stem/progenitor cells, which showed NF-κB activation and early lymphoid priming, being selectively skewed toward B-cell differentiation. These cells accumulated in extranodal tissues and gave rise to clonal tumors recapitulating the principal clinical, biological, and molecular genetic features of MALT lymphoma. Deletion of p53 gene accelerated tumor onset and induced transformation of MALT lymphoma to activated B-cell diffuse large-cell lymphoma (ABC-DLBCL). Treatment of MALT1-induced lymphomas with a specific inhibitor of MALT1 proteolytic activity decreased cell viability, indicating that endogenous Malt1 signaling was required for tumor cell survival. Our study shows that human-like lymphomas can be modeled in mice by targeting MALT1 expression to hematopoietic stem/progenitor cells, demonstrating the oncogenic role of MALT1 in lymphomagenesis. Furthermore, this work establishes a molecular link between MALT lymphoma and ABC-DLBCL, and provides mouse models to test MALT1 inhibitors. Finally, our results suggest that hematopoietic stem/progenitor cells may be involved in the pathogenesis of human mature B-cell lymphomas.


Assuntos
Caspases/genética , Células-Tronco Hematopoéticas/metabolismo , Linfoma/patologia , Proteínas de Neoplasias/genética , Oncogenes , Animais , Humanos , Camundongos , Camundongos Transgênicos , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , NF-kappa B/metabolismo , Transcrição Genética
19.
Blood ; 119(23): 5478-91, 2012 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-22517897

RESUMO

LMO2 regulates gene expression by facilitating the formation of multipartite DNA-binding complexes. In B cells, LMO2 is specifically up-regulated in the germinal center (GC) and is expressed in GC-derived non-Hodgkin lymphomas. LMO2 is one of the most powerful prognostic indicators in diffuse large B-cell (DLBCL) patients. However, its function in GC B cells and DLBCL is currently unknown. In this study, we characterized the LMO2 transcriptome and transcriptional complex in DLBCL cells. LMO2 regulates genes implicated in kinetochore function, chromosome assembly, and mitosis. Overexpression of LMO2 in DLBCL cell lines results in centrosome amplification. In DLBCL, the LMO2 complex contains some of the traditional partners, such as LDB1, E2A, HEB, Lyl1, ETO2, and SP1, but not TAL1 or GATA proteins. Furthermore, we identified novel LMO2 interacting partners: ELK1, nuclear factor of activated T-cells (NFATc1), and lymphoid enhancer-binding factor1 (LEF1) proteins. Reporter assays revealed that LMO2 increases transcriptional activity of NFATc1 and decreases transcriptional activity of LEF1 proteins. Overall, our studies identified a novel LMO2 transcriptome and interactome in DLBCL and provides a platform for future elucidation of LMO2 function in GC B cells and DLBCL pathogenesis.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Linfócitos B/metabolismo , Proteínas com Domínio LIM/genética , Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas/genética , Transcriptoma , Linfócitos B/patologia , Sequência de Bases , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células , Centrossomo/ultraestrutura , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Difuso de Grandes Células B/patologia , Dados de Sequência Molecular , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/genética
20.
Blood ; 118(20): 5517-27, 2011 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-21937691

RESUMO

PIM serine/threonine kinases are overexpressed, translocated, or amplified in multiple B-cell lymphoma types. We have explored the frequency and relevance of PIM expression in different B-cell lymphoma types and investigated whether PIM inhibition could be a rational therapeutic approach. Increased expression of PIM2 was detected in subsets of mantle cell lymphoma, diffuse large B-cell lymphoma (DLBLC), follicular lymphoma, marginal zone lymphoma-mucosa-associated lymphoid tissue type, chronic lymphocytic leukemia, and nodal marginal zone lymphoma cases. Increased PIM2 protein expression was associated with an aggressive clinical course in activated B-like-DLBCL patients. Pharmacologic and genetic inhibition of PIM2 revealed p4E-BP1(Thr37/46) and p4E-BP1(Ser65) as molecular biomarkers characteristic of PIM2 activity and indicated the involvement of PIM2 kinase in regulating mammalian target of rapamycin complex 1. The simultaneous genetic inhibition of all 3 PIM kinases induced changes in apoptosis and cell cycle. In conclusion, we show that PIM2 kinase inhibition is a rational approach in DLBCL treatment, identify appropriate biomarkers for pharmacodynamic studies, and provide a new marker for patient stratification.


Assuntos
Inibidores Enzimáticos/farmacologia , Terapia Genética/métodos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Linfonodos/patologia , Linfoma Folicular/genética , Linfoma Folicular/patologia , Linfoma Folicular/terapia , Linfoma Difuso de Grandes Células B/patologia , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , Linfoma de Célula do Manto/terapia , Tonsila Palatina/patologia , Fosfoproteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Proteína de Morte Celular Associada a bcl/metabolismo
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