RESUMO
Nodal marginal zone lymphoma (NMZL) is a small B-cell neoplasm whose molecular pathogenesis is still essentially unknown and whose differentiation from other small B-cell lymphomas is hampered by the lack of specific markers. We have analyzed gene expression, miRNA profile, and copy number data from 15 NMZL cases. For comparison, 16 follicular lymphomas (FLs), 9 extranodal marginal zone lymphomas, and 8 reactive lymph nodes and B-cell subtypes were included. The results were validated by quantitative RT-PCR in an independent series, including 61 paraffin-embedded NMZLs. NMZL signature showed an enriched expression of gene sets identifying interleukins, integrins, CD40, PI3K, NF-κB, and TGF-ß, and included genes expressed by normal marginal zone cells and memory B cells. The most highly overexpressed genes were SYK, TACI, CD74, CD82, and CDC42EP5. Genes linked to G(2)/M and germinal center were down-regulated. Comparison of the gene expression profiles of NMZL and FL showed enriched expression of CHIT1, TGFB1, and TACI in NMZL, and BCL6, LMO2, and CD10 in FL. NMZL displayed increased expression of miR-221, miR-223, and let-7f, whereas FL strongly expressed miR-494. Our study identifies new candidate diagnostic molecules for NMZL and reveals survival pathways activated in NMZL.
Assuntos
Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma Folicular/genética , MicroRNAs/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Técnicas Imunoenzimáticas , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Splenic marginal zone lymphoma is a small B-cell neoplasm whose molecular pathogenesis is still essentially unknown and whose differentiation from other small B-cell lymphomas is hampered by the lack of specific markers. We have analyzed the gene expression and miRNA profiles of 31 splenic marginal zone lymphoma cases. For comparison, 7 spleens with reactive lymphoid hyperplasia, 10 spleens infiltrated by chronic lymphocytic leukemia, 12 spleens with follicular lymphoma, 6 spleens infiltrated by mantle cell lymphoma and 15 lymph nodes infiltrated by nodal marginal zone lymphoma were included. The results were validated by qRT-PCR in an independent series including 77 paraffin-embedded splenic marginal zone lymphomas. The splenic marginal zone lymphoma miRNA signature had deregulated expression of 51 miRNAs. The most highly overexpressed miRNAs were miR-155, miR-21, miR-34a, miR-193b and miR-100, while the most repressed miRNAs were miR-377, miR-27b, miR-145, miR-376a and miR-424. MiRNAs located in 14q32-31 were underexpressed in splenic marginal zone lymphoma compared with reactive lymphoid tissues and other B-cell lymphomas. Finally, the gene expression data were integrated with the miRNA profile to identify functional relationships between genes and deregulated miRNAs. Our study reveals miRNAs that are deregulated in splenic marginal zone lymphoma and identifies new candidate diagnostic molecules for splenic marginal zone lymphoma.
Assuntos
Linfoma de Zona Marginal Tipo Células B/genética , MicroRNAs/análise , MicroRNAs/genética , Neoplasias Esplênicas/genética , Adulto , Idoso , Feminino , Humanos , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo Real , TranscriptomaRESUMO
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 , Proteínas de Ciclo Celular , 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/metabolismoAssuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Doença de Hodgkin/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Humanos , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Células Tumorais CultivadasRESUMO
PURPOSE: We observed three apparently unrelated and geographically separate Arab families with Lafora disease in Israel and the Palestinian territories. METHODS: We clinically evaluated the families and analyzed their DNA for EPM2A mutations. RESULTS: Of seven individuals with Lafora disease, the clinical onset varied from 13 to 20 years. All three families shared the same novel homozygous deletion in EPM2A. Haplotype analysis around the deletion showed that the families shared a common homozygous haplotype. The boundaries of this haplotype varied between families and even within one family. CONCLUSIONS: We conclude that considerable variability in the age at onset of Lafora disease can occur within families. Identical mutations can be associated with the classic adolescent presentation, as well as late-onset cases. Haplotype analysis suggests that this EPM2A mutation arose many generations previously, so it may be of importance for cases distributed more widely in the Middle East.