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1.
Clin Exp Immunol ; 216(1): 45-54, 2024 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-38133636

RESUMO

Cold agglutinin disease (CAD) is a rare B-cell lymphoproliferative disorder of the bone marrow, manifested by autoimmune hemolytic anemia caused by binding of monoclonal IgM autoantibodies to the I antigen. Underlying genetic changes have previously been reported, but their impact on gene expression profile has been unknown. Here, we define differentially expressed genes in CAD B cells. To unravel downstream alteration in cellular pathways, gene expression by RNA sequencing was undertaken. Clonal B-cell samples from 12 CAD patients and IgM-expressing memory B cells from 4 healthy individuals were analyzed. Differential expression analysis and filtering resulted in 93 genes with significant differential expression. Top upregulated genes included SLC4A1, SPTA1, YBX3, TESC, HBD, AHSP, TRAF1, HBA2, RHAG, CA1, SPTB, IL10, UBASH3B, ALAS2, HBA1, CRYM, RGCC, KANK2, and IGHV4-34. They were upregulated at least 8-fold, while complement receptor 1 (CR1/CD35) was downregulated 11-fold in clonal CAD B cells compared to control B cells. Flow cytometry analyses further confirmed reduced CR1 (CD35) protein expression by clonal CAD IgM+ B cells compared to IgM+ memory B cells in controls. CR1 (CD35) is an important negative regulator of B-cell activation and differentiation. Therefore, reduced CR1 (CD35) expression may increase activation, proliferation, and antibody production in CAD-associated clonal B cells.


Assuntos
Anemia Hemolítica Autoimune , Humanos , Anemia Hemolítica Autoimune/genética , Anemia Hemolítica Autoimune/metabolismo , Regulação para Baixo , Receptores de Complemento 3b/genética , Linfócitos B , Imunoglobulina M , Perfilação da Expressão Gênica , Proteínas Sanguíneas/genética , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismo , 5-Aminolevulinato Sintetase/genética , 5-Aminolevulinato Sintetase/metabolismo
2.
Blood ; 129(6): 759-770, 2017 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-28011673

RESUMO

Kinases downstream of B-cell antigen receptor (BCR) represent attractive targets for therapy in non-Hodgkin lymphoma (NHL). As clinical responses vary, improved knowledge regarding activation and regulation of BCR signaling in individual patients is needed. Here, using phosphospecific flow cytometry to obtain malignant B-cell signaling profiles from 95 patients representing 4 types of NHL revealed a striking contrast between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) tumors. Lymphoma cells from diffuse large B-cell lymphoma patients had high basal phosphorylation levels of most measured signaling nodes, whereas follicular lymphoma cells represented the opposite pattern with no or very low basal levels. MCL showed large interpatient variability in basal levels, and elevated levels for the phosphorylated forms of AKT, extracellular signal-regulated kinase, p38, STAT1, and STAT5 were associated with poor outcome. CLL tumors had elevated basal levels for the phosphorylated forms of BCR-signaling nodes (Src family tyrosine kinase, spleen tyrosine kinase [SYK], phospholipase Cγ), but had low α-BCR-induced signaling. This contrasted MCL tumors, where α-BCR-induced signaling was variable, but significantly potentiated as compared with the other types. Overexpression of CD79B, combined with a gating strategy whereby signaling output was directly quantified per cell as a function of CD79B levels, confirmed a direct relationship between surface CD79B, immunoglobulin M (IgM), and IgM-induced signaling levels. Furthermore, α-BCR-induced signaling strength was variable across patient samples and correlated with BCR subunit CD79B expression, but was inversely correlated with susceptibility to Bruton tyrosine kinase (BTK) and SYK inhibitors in MCL. These individual differences in BCR levels and signaling might relate to differences in therapy responses to BCR-pathway inhibitors.


Assuntos
Regulação Neoplásica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/genética , Linfoma Folicular/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma de Célula do Manto/genética , Fosfoproteínas/genética , Receptores de Antígenos de Linfócitos B/genética , Tirosina Quinase da Agamaglobulinemia , Antígenos CD79/genética , Antígenos CD79/metabolismo , Diagnóstico Diferencial , Citometria de Fluxo , Humanos , Imunoglobulina M/genética , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Linfoma Folicular/diagnóstico , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/metabolismo , Linfoma de Célula do Manto/patologia , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Fosfolipase C gama/genética , Fosfolipase C gama/metabolismo , Fosfoproteínas/metabolismo , Fosforilação , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Análise de Célula Única , Quinase Syk/genética , Quinase Syk/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Quinases da Família src/genética , Quinases da Família src/metabolismo
3.
Br J Haematol ; 183(2): 225-234, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30080252

RESUMO

Patients with mantle cell lymphoma (MCL) generally have a dismal prognosis. Intensified induction treatment with rituximab and high dose cytarabine (R_HDAC), and consolidation with high-dose therapy with autologous stem cell support has resulted in 10-year overall survival (OS) higher than 60%. However, the clinical course varies. Diagnostic tools capable of stratifying patients include the MCL International Prognostic Index (MIPI), gene expression-based proliferation signature, Ki-67 proliferation index or tumour cell morphology. Here, we tested the performance of a newly developed Nanostring-based RNA expression-based proliferation assay (MCL35) on formalin-fixed paraffin-embedded tumour tissue from younger patients recruited in or treated according to Nordic MCL protocols compared to the prognosticators listed above. Seventy-four patients were included and the assay performed well in all cases except four, which had inadequate RNA quality. The patients were evenly distributed in the MCL35 low-, intermediate- and high-risk categories. MCL35 low- and intermediate- risk groups had overlapping progression-free survival (PFS), while patients in the high-risk category had significantly inferior PFS. Combining MCL35 with MIPI or the MIPI-C (MIPI with the addition of binary Ki67 score +/-30%) showed a better discrimination than either assessment alone. In conclusion, the MCL35 assay alone or combined with MIPI or MIPI-C scores can identify patients who still have a dismal outcome despite intensified treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Adulto , Idoso , Biópsia , Proliferação de Células , Feminino , Perfilação da Expressão Gênica/métodos , Transplante de Células-Tronco Hematopoéticas , Humanos , Estimativa de Kaplan-Meier , Linfoma de Célula do Manto/diagnóstico , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , RNA Neoplásico/genética , Fatores de Risco
4.
Acta Derm Venereol ; 97(9): 1081-1086, 2017 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-28597017

RESUMO

Folliculotropic mycosis fungoides (FMF), a variant of mycosis fungoides (MF) with distinct clinical features, is characterized by infiltration of malignant T cells in hair follicles. This raises the hypothesis that antigens in the hair follicle may contribute to the pathogenesis of FMF. T-cell receptor ß gene (TRB) sequences as well as dendritic cell subsets in patients with FMF (n = 21) and control patients with MF (n = 20) were studied to explore this hypothesis. A recurrent usage of the TRB junctional genes TRBJ2-1 and TRBJ2-7 was found in patients with FMF compared with those with MF. These genes contribute to an amino acid motif in the complementarity-determining region 3 (CDR3) of the T-cell receptor. This motif was previously found in T cells stimulated by lipids bound to CD1 on antigen-presenting cells. Additional immunohistochemical analysis revealed abundant CD1c- and CD1a- expressing dendritic cells in FMF. The combined findings support a role for lipid-antigen stimulation in FMF.


Assuntos
Antígenos CD1/análise , Glicoproteínas/análise , Micose Fungoide/química , Micose Fungoide/patologia , Estudos de Casos e Controles , Regiões Determinantes de Complementaridade/análise , Células Dendríticas/química , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T , Folículo Piloso/química , Folículo Piloso/patologia , Humanos , Imuno-Histoquímica , Linfoma Cutâneo de Células T/química , Linfoma Cutâneo de Células T/genética , Linfoma Cutâneo de Células T/patologia , Micose Fungoide/genética , Neoplasias Cutâneas/química , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
5.
Blood ; 123(7): 1051-4, 2014 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-24357726

RESUMO

Transformation of follicular lymphoma (FL) to a more aggressive disease is associated with rapid progression and death. Existing molecular markers for transformation are few and their clinical impact is limited. Here, we report on a whole-genome study of DNA copy numbers and gene expression profiles in serial FL biopsies. We identified 698 genes with high correlation between gene expression and copy number, and the molecular network most enriched for these cis-associated genes. This network includes 14 cis-associated genes directly related to the nuclear factor κB (NF-κB) pathway. For each of these 14 genes, the correlated NF-κB target genes were identified and corresponding expression scores were defined. The scores for 6 of the cis-associated NFκB pathway genes (BTK, IGBP1, IRAK1, ROCK1, TMED7-TICAM2, and TRIM37) were significantly associated with transformation. The results suggest that genes regulating B-cell survival and activation are involved in transformation of FL.


Assuntos
Transformação Celular Neoplásica/genética , Linfoma Folicular/genética , Transcriptoma , Dosagem de Genes , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Linfoma Folicular/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Integração de Sistemas
7.
BMC Genomics ; 16 Suppl 7: S12, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26099425

RESUMO

BACKGROUND: High-throughput in vivo protein-DNA interaction experiments are currently widely used in gene regulation studies. Hitherto, comprehensive data analysis remains a challenge and for that reason most computational methods only consider the top few hundred or thousand strongest protein binding sites whereas weak protein binding sites are completely ignored. RESULTS: A new biophysical model of protein-DNA interactions, BayesPI2+, was developed to address the above-mentioned challenges. BayesPI2+ can be run in either a serial computation model or a parallel ensemble learning framework. BayesPI2+ allowed us to analyze all binding sites of the transcription factors, including weak binding that cannot be analyzed by other models. It is evaluated in both synthetic and real in vivo protein-DNA binding experiments. Analysing ESR1 and SPIB in breast carcinoma and activated B cell-like diffuse large B-cell lymphoma cell lines, respectively, revealed that the concerted binding to high and low affinity sites correlates best with gene expression. CONCLUSIONS: BayesPI2+ allows us to analyze transcription factor binding on a larger scale than hitherto achieved. By this analysis, we were able to demonstrate that genes are regulated by concerted binding to high and low affinity binding sites. The program and output results are publicly available at: http://folk.uio.no/junbaiw/BayesPI2Plus.


Assuntos
Neoplasias da Mama/metabolismo , DNA/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Algoritmos , Sítios de Ligação , Linhagem Celular Tumoral , Biologia Computacional/métodos , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Receptor alfa de Estrogênio/química , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Modelos Teóricos , Fatores de Transcrição/genética
8.
Haematologica ; 99(3): 497-504, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24143001

RESUMO

Primary chronic cold agglutinin disease is a rare hemolytic disease mediated by monoclonal IGHV4-34-encoded cold agglutinins with a predominant specificity for the blood group antigen I. Bone marrow from 54 patients was studied to type the underlying lymphoproliferative disorder better. Bone marrow biopsies showed circumscribed intra-parenchymatous nodules with small monotonous monoclonal B cells in 40/54 patients (median infiltration: 10% of marrow cells) with a CD20(+), IgMs(+), IgDs(+), CD27(+), CD5(-/+), CD11c(-), CD23(-), CD38(-) immunophenotype. Neither plasmacytoid cytological features nor expression of plasma cell differentiation-associated transcription factors MUM1, XBP1 and BLIMP1 were noted in these B cells. However, a limited number of mature monoclonal IgM(+), IgD(-) plasma cells were present outside the lymphoid nodules and were diffusely scattered throughout the marrow. Of interest, the MYD88 L265P mutation, typical of lymphoplasmacytic lymphoma, was not detected (17/17 cases). Somatically mutated monoclonal IGHV4-34 gene rearrangement was demonstrated in eight patients with frozen samples (mean sequence homology 95.4%). However, mutations of BCL6 intron 1 were not demonstrated, except in one patient, suggesting that the lymphoma cells had not matured in the germinal center. In conclusion, cold agglutinin-associated lymphoproliferative disease displays homogeneous histological and immunophenotypic features. The absence of plasmacytoid cells, the presence of plasma cells predominantly outside the nodular lymphoid infiltrates, IGHV4-34 restriction and absence of MYD88 L265P mutation strongly suggest that cold agglutinin-associated lymphoproliferative disease is a distinct entity that is different from lymphoplasmacytic lymphoma.


Assuntos
Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Medula Óssea/metabolismo , Medula Óssea/patologia , Crioglobulinas/imunologia , Crioglobulinas/metabolismo , Proteínas de Ligação a DNA/genética , Diagnóstico Diferencial , Feminino , Seguimentos , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Pesadas de Imunoglobulinas/metabolismo , Imuno-Histoquímica , Imunofenotipagem , Linfoma de Células B/diagnóstico , Linfoma de Células B/genética , Linfoma de Células B/imunologia , Linfoma de Células B/metabolismo , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/metabolismo , Masculino , Pessoa de Meia-Idade , Fator 88 de Diferenciação Mieloide/genética , Proteínas Proto-Oncogênicas c-bcl-6 , Baço/metabolismo , Baço/patologia , Macroglobulinemia de Waldenstrom/diagnóstico
9.
Am J Dermatopathol ; 36(12): 972-6, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25140661

RESUMO

Multiple distinct T-cell clones have been demonstrated in a subset of mycosis fungoides (MF), but have so far not been documented in folliculotropic MF, a clinical and histological variant of MF. We analyzed T-cell receptor (TCR) gene rearrangements in 8 patients with folliculotropic MF with multiple biopsies (range, 2-5) taken during the course of disease. Two patients had disease stage IA-IIA, 5 stage IIB-IVA, whereas data were not available for 1 patient. TCR ß and γ gene rearrangements were analyzed according to the BIOMED-2 PCR protocol. Multiple clonal TCR gene rearrangements indicating more than 1 T-cell clone were found in 5 patients. Although the number of patients is small, the finding of multiple distinct T-cell clones in 5 out of 8 patients suggests that chronic T-cell stimulation contributes to the development of folliculotropic MF.


Assuntos
Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T , Rearranjo Gênico da Cadeia gama dos Receptores de Antígenos dos Linfócitos T , Micose Fungoide/genética , Micose Fungoide/patologia , Adulto , Idoso , Células Clonais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Micose Fungoide/imunologia
12.
Blood ; 118(12): 3331-9, 2011 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-21725051

RESUMO

One-third of all splenic marginal zone lymphomas (SMZL) use the IgH VH1-02 gene. These cases are usually not associated with hepatitis C virus infection. Of interest, the rearranged VH1-02 genes display similar complementarity determining regions 3, a finding confirmed by our study. The latter suggests that these SMZL may produce antibodies with similar reactivity. We produced recombinant antibodies from 5 SMZL cases with VH1-02 gene rearrangement to study the binding reactivity of these antibodies. Surprisingly, the recombinant antibodies demonstrated poly- and self-reactivity as demonstrated by their reactivity with nuclear, cytoplasmic, as well as membranous antigens expressed by human cells and by reactivity with human serum. This polyreactivity was specific as demonstrated by ELISA. The antibodies did not react with proteins on the cell surface that are induced by apoptosis as shown for antibodies produced by chronic lymphatic leukemia with VH1-02 gene rearrangement. The results indicate that a common subset of SMZL arises from polyreactive B cells, a subset of marginal zone B cells that are important in the immunologic defense against infection.


Assuntos
Anticorpos/metabolismo , Rearranjo Gênico/imunologia , Cadeias Leves de Imunoglobulina/metabolismo , Região Variável de Imunoglobulina/metabolismo , Linfoma de Zona Marginal Tipo Células B/imunologia , Proteínas Recombinantes/metabolismo , Baço/imunologia , Neoplasias Esplênicas/imunologia , Anticorpos/genética , Anticorpos/imunologia , Especificidade de Anticorpos , Proteínas Sanguíneas/imunologia , Proteínas Sanguíneas/metabolismo , Clonagem Molecular , Ensaio de Imunoadsorção Enzimática , Feminino , Células HEK293 , Hepacivirus/crescimento & desenvolvimento , Hepacivirus/imunologia , Hepatite C/imunologia , Hepatite C/virologia , Humanos , Cadeias Leves de Imunoglobulina/genética , Cadeias Leves de Imunoglobulina/imunologia , Região Variável de Imunoglobulina/genética , Região Variável de Imunoglobulina/imunologia , Imuno-Histoquímica , Imunofenotipagem , Isoantígenos/imunologia , Isoantígenos/metabolismo , Cariotipagem , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/patologia , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia , Baço/metabolismo , Baço/patologia , Neoplasias Esplênicas/genética , Neoplasias Esplênicas/patologia , Transfecção
13.
Blood ; 116(9): 1489-97, 2010 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-20505157

RESUMO

Our aim was to examine the genetics of clonal evolution in follicular lymphoma (FL) and to identify genetic alterations associated with disease progression. A total of 100 biopsies from 44 patients diagnosed with t(14;18)-positive FL were examined by array comparative genomic hybridization. In 20 patients the patterns of somatic hypermutations (SHMs) in the variable region of heavy chain gene were additionally analyzed. Gain of chromosome X in male samples was a marker for poor outcome (P < .01). Gains involving chromosome 2, 3q, and 5 were exclusively present in FL biopsies from cases with higher grade transformation and were among the copy number alterations (CNAs) associated with inferior survival. Although we noted a trend for increasing genomic complexity in initial versus late FL samples, the overall frequencies of CNAs in initial and late FL biopsies showed a surprisingly stable pattern through the course of the disease. In 27 of cases the initial samples harbored CNAs that were absent in relapse samples, indicating that tumor cell clones at relapse were not direct descendants of initially dominating clones. The pattern of SHMs confirmed parallel development of tumor cell clones in 14 cases. Our findings support the hypothesis of common progenitor cells in FL.


Assuntos
Transformação Celular Neoplásica , Aberrações Cromossômicas , Células Clonais/patologia , Linfoma Folicular/genética , Linfoma Difuso de Grandes Células B/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Cromossomos Humanos Par 2/genética , Cromossomos Humanos Par 3/genética , Cromossomos Humanos Par 5/genética , Hibridização Genômica Comparativa , DNA de Neoplasias/genética , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Taxa de Sobrevida , Translocação Genética
14.
Comput Struct Biotechnol J ; 20: 1726-1742, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35495111

RESUMO

A major challenge in human genetics is of the analysis of the interplay between genetic and epigenetic factors in a multifactorial disease like cancer. Here, a novel methodology is proposed to investigate genome-wide regulatory mechanisms in cancer, as studied with the example of follicular Lymphoma (FL). In a first phase, a new machine-learning method is designed to identify Differentially Methylated Regions (DMRs) by computing six attributes. In a second phase, an integrative data analysis method is developed to study regulatory mutations in FL, by considering differential methylation information together with DNA sequence variation, differential gene expression, 3D organization of genome (e.g., topologically associated domains), and enriched biological pathways. Resulting mutation block-gene pairs are further ranked to find out the significant ones. By this approach, BCL2 and BCL6 were identified as top-ranking FL-related genes with several mutation blocks and DMRs acting on their regulatory regions. Two additional genes, CDCA4 and CTSO, were also found in top rank with significant DNA sequence variation and differential methylation in neighboring areas, pointing towards their potential use as biomarkers for FL. This work combines both genomic and epigenomic information to investigate genome-wide gene regulatory mechanisms in cancer and contribute to devising novel treatment strategies.

15.
PLoS One ; 17(8): e0273280, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36037157

RESUMO

Neuroblastoma (NBL), one of the main death-causing cancers in children, is known for its remarkable genetic heterogeneity and varied patient outcome spanning from spontaneous regression to widespread disease. Specific copy number variations and single gene rearrangements have been proven to be associated with biological behavior and prognosis; however, there is still an unmet need to enlarge the existing armamentarium of prognostic and therapeutic targets. We performed whole exome sequencing (WES) of samples from 18 primary tumors and six relapse samples originating from 18 NBL patients. Our cohort consists of 16 high-risk, one intermediate, and one very low risk patient. The obtained results confirmed known mutational hotspots in ALK and revealed other non-synonymous variants of NBL-related genes (TP53, DMD, ROS, LMO3, PRUNE2, ERBB3, and PHOX2B) and of genes cardinal for other cancers (KRAS, PIK3CA, and FLT3). Beyond, GOSeq analysis determined genes involved in biological adhesion, neurological cell-cell adhesion, JNK cascade, and immune response of cell surface signaling pathways. We were able to identify novel coding variants present in more than one patient in nine biologically relevant genes for NBL, including TMEM14B, TTN, FLG, RHBG, SHROOM3, UTRN, HLA-DRB1, OR6C68, and XIRP2. Our results may provide novel information about genes and signaling pathways relevant for the pathogenesis and clinical course in high-risk NBL.


Assuntos
Variações do Número de Cópias de DNA , Neuroblastoma , Criança , Humanos , Proteínas de Membrana Transportadoras/genética , Mutação , Recidiva Local de Neoplasia , Neuroblastoma/genética , Neuroblastoma/metabolismo , Sequenciamento do Exoma/métodos
18.
Pigment Cell Melanoma Res ; 33(3): 446-457, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31660681

RESUMO

MX2 protein is a dynamin-like GTPase2 that has recently been identified as an interferon-induced restriction factor of HIV-1 and other primate lentiviruses. A single nucleotide polymorphism (SNP), rs45430, in an intron of the MX2 gene, was previously reported as a novel melanoma susceptibility locus in genome-wide association studies. Functionally, however, it is still unclear whether and how MX2 contributes to melanoma susceptibility and tumorigenesis. Here, we show that MX2 is differentially expressed in melanoma tumors and cell lines, with most metastatic cell lines showing lower MX2 expression than primary melanoma cell lines and melanocytes. Furthermore, high expression of MX2 RNA in primary melanoma tumors is associated with better patient survival. Overexpression of MX2 reduces in vivo proliferation partially through inhibition of AKT activation, suggesting that it can act as a tumor suppressor in melanoma. However, we have also identified a subset of melanoma cell lines with high endogenous MX2 expression where downregulation of MX2 leads to reduced proliferation. In these cells, MX2 downregulation interfered with DNA replication and cell cycle processes. Collectively, our data for the first time show that MX2 is functionally involved in the regulation of melanoma proliferation but that its function is context-dependent.


Assuntos
Ciclo Celular , Melanoma/patologia , Proteínas de Resistência a Myxovirus/metabolismo , Animais , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Melanoma/genética , Camundongos Nus , Proteínas de Resistência a Myxovirus/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
19.
Cell Rep ; 32(12): 108171, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32966799

RESUMO

High-risk neuroblastomas typically display an undifferentiated or poorly differentiated morphology. It is therefore vital to understand molecular mechanisms that block the differentiation process. We identify an important role for oncogenic ALK-ERK1/2-SP1 signaling in the maintenance of undifferentiated neural crest-derived progenitors through the repression of DLG2, a candidate tumor suppressor gene in neuroblastoma. DLG2 is expressed in the murine "bridge signature" that represents the transcriptional transition state when neural crest cells or Schwann cell precursors differentiate to chromaffin cells of the adrenal gland. We show that the restoration of DLG2 expression spontaneously drives neuroblastoma cell differentiation, highlighting the importance of DLG2 in this process. These findings are supported by genetic analyses of high-risk 11q deletion neuroblastomas, which identified genetic lesions in the DLG2 gene. Our data also suggest that further exploration of other bridge genes may help elucidate the mechanisms underlying the differentiation of NC-derived progenitors and their contribution to neuroblastomas.


Assuntos
Quinase do Linfoma Anaplásico/genética , Diferenciação Celular , Deleção Cromossômica , Cromossomos Humanos Par 11/genética , Guanilato Quinases/genética , Neuroblastoma/genética , Neuroblastoma/patologia , Proteínas Supressoras de Tumor/genética , Adrenérgicos/metabolismo , Animais , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/patologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Cromafins/efeitos dos fármacos , Células Cromafins/metabolismo , Células Cromafins/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Guanilato Quinases/metabolismo , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Fator de Crescimento Neural/farmacologia , Neurônios/metabolismo , Neurônios/patologia , Fenótipo , Prognóstico , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Células de Schwann/patologia , Fator de Transcrição Sp1/metabolismo , Transcrição Gênica/efeitos dos fármacos , Resultado do Tratamento , Tretinoína/farmacologia , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima/efeitos dos fármacos
20.
Tidsskr Nor Laegeforen ; 129(22): 2352-6, 2009 Nov 19.
Artigo em Norueguês | MEDLINE | ID: mdl-19935935

RESUMO

BACKGROUND: Malignant lymphomas comprise a heterogeneous group of non-solid tumors originating in lymphocytes at different maturation stages. The diagnosis is based on a traditional histopathological diagnostic procedure supplemented with immunophenotyping, cytogenetics, molecular genetic analyses and clinical information. This article describes experimental molecular diagnostics, mainly based on microarray-based gene expression technology. MATERIAL AND METHODS: Results achieved through an international multicentre project (headed by the National Cancer Institute in the USA), in which the Norwegian Radium Hospital has taken part as the only Nordic institution, are summarized. The findings are discussed in light of other relevant studies identified through a non-systematic search in PubMed. RESULTS: New clinically relevant subgroups of malignant B-cell lymphomas have been characterized. Retrospective survival analyses have shown correlations between gene expression profiles and patient outcome and have provided important biological knowledge, which has led to new targeted treatments (currently being tested in clinical studies). INTERPRETATION: As a supplement to today's diagnostics, molecular diagnostics yields an improved diagnostic precision and opens up for new treatment possibilities for patients with malignant lymphomas.


Assuntos
Perfilação da Expressão Gênica , Linfoma de Células B/diagnóstico , Linfoma/diagnóstico , Técnicas de Diagnóstico Molecular , Linfoma de Burkitt/classificação , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/patologia , Feminino , Humanos , Linfoma/classificação , Linfoma/patologia , Linfoma de Células B/classificação , Linfoma de Células B/patologia , Linfoma Folicular/classificação , Linfoma Folicular/diagnóstico , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/classificação , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/patologia , Masculino , MicroRNAs/genética , Análise de Sequência com Séries de Oligonucleotídeos , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
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