RESUMEN
The interaction between CD40, and its ligand, CD154, is essential for the development of humoral and cellular immune responses. The selective inhibition or activation of this pathway forms the basis for the development of new therapeutics against immunologically based diseases and malignancies. We are developing a gene fusion of Salmonella typhi OmpC protein expressing the CD154 Tyr140-Ser-149 amino acid strand. This OmpC-CD154 binds CD40 and activates B cells. In this study, we demonstrate that OmpC-CD154p treatment inhibits cell growth, proliferation and induced apoptosis in the B-NHL cell lines Raji and Ramos. The Bcl-2 family proteins were regulated and the Bcl-6 and YY1 oncoproteins were inhibited. p38 MAPK activation is an important mechanism underlying the effect on proliferation and apoptosis mediated by this fusion protein. This study establishes a basis for the possible use of fusion protein OmpC-CD154 as an alternative treatment for B-NHL.
Asunto(s)
Caspasas/metabolismo , Péptidos/farmacología , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Factor de Transcripción YY1/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Antígenos CD40/metabolismo , Ligando de CD40/química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Imitación Molecular , Péptidos/química , Porinas/químicaRESUMEN
High-grade B-cell lymphomas with rearrangement of MYC, BCL-2 and/or BCL-6 were introduced by the update of the WHO classification of lymphoid neoplasms. They usually present unique morphological and molecular characteristics, with an aggressive clinical outcome and worse prognosis. We report a 48 year-old female patient presenting with B symptoms and enlarged lymph nodes. Blood count showed pancytopenia and peripheral blood smears showed large lymphoid cells, some with nuclei and vacuoles. LDH was 3524 g/L and serum calcium was 11.5 mg/dL. Flow cytometry immunophenotyping showed pathological mature B lymphocytes. Protein electrophoresis showed a slight monoclonal peak. The biopsy disclosed a triple expressor diffuse large B-cell lymphoma, arising from germinal center. FISH was positive for MYC, BCL-2 and BCL-6 (triple hit) with a clonal evolution. Conventional cytogenetics showed a complex karyotype. Chemotherapy was started with R-CHOP (Rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone). She developed impaired consciousness; the brain CT scan showed a large brain mass. The patient died within 3 weeks.
Asunto(s)
Humanos , Femenino , Persona de Mediana Edad , Translocación Genética/genética , Linfoma de Células B Grandes Difuso/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-6/genética , Hipercalcemia/etiología , Tomografía Computarizada por Rayos X , Linfoma de Células B Grandes Difuso/complicaciones , Linfoma de Células B Grandes Difuso/patología , Resultado Fatal , CariotipoRESUMEN
Adipose tissue is a key determinant of whole-body metabolism and energy homeostasis. Unravelling the transcriptional regulatory process during adipogenesis is therefore highly relevant from a biomedical perspective. In these studies, zinc finger protein B-cell lymphoma 6 (Bcl6) was demonstrated to have a role in early adipogenesis of mesenchymal stem cells. Bcl6 is enriched in preadipose versus non-preadipose fibroblasts and shows upregulated expression in the early stage of adipogenesis. Gain- and loss-of-function studies revealed that Bcl6 acts as a key regulator of adipose commitment and differentiation both in vitro and ex vivo RNAi-mediated knockdown of Bcl6 in C3H10T1/2 cells greatly inhibited adipogenic potential, whereas Bcl6 overexpression enhanced adipogenic differentiation. This transcription factor also directly or indirectly targets and controls the expression of some early and late adipogenic regulators (i.e. Zfp423, Zfp467, KLF15, C/EBPδ, C/EBPα and PPARγ). We further identified that Bcl6 transactivated the signal transducers and activators of transcription 1 (STAT1), which was determined as a required factor for adipogenesis. Moreover, overexpression of STAT1 rescued the impairment of adipogenic commitment and differentiation induced by Bcl6 knockdown in C3H10T1/2 cells, thereby confirming that STAT1 is a downstream direct target of Bcl6. This study identifies Bcl6 as a positive transcriptional regulator of early adipose commitment.
Asunto(s)
Adipogénesis , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Factor de Transcripción STAT1/genética , Células 3T3-L1 , Tejido Adiposo/citología , Animales , Diferenciación Celular , Regulación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Células Madre Mesenquimatosas , Ratones , Células 3T3 NIH , Regiones Promotoras Genéticas , Proteínas Proto-Oncogénicas c-bcl-6/genética , Activación TranscripcionalRESUMEN
INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is a molecularly heterogeneous disease defined by different cellular origins and mechanisms of oncogenic activation. Approximately 10% of DLBCL cases harbor a MYC rearrangement and this has been associated with a more aggressive clinical course following standard therapy. AREAS COVERED: So-called 'double-hit lymphomas' (DHL) or 'triple hit lymphomas' (THL) occur when MYC is concurrently rearranged with BCL2 and/or BCL6. These tumors are characterized by high proliferation rate and a very poor outcome following standard R-CHOP (rituximab, cyclophosphamide, doxorubicin vincristine and prednisone) therapy, in most (though not all) studies that have looked at this. Though there is a paucity of published experience with other chemotherapy regimens, there is emerging evidence that more intensive approaches may improve outcome. Recently, there has been a lot of focus in the literature on 'double-expresser lymphomas' (DEL) with high MYC, BCL2 and/or BCL6 expression but typically without rearrangements of these genes. These DEL cases, have a poor outcome with R-CHOP and there is little consensus on how they should be approached. Expert commentary: This review will focus on the biology and treatment of DHL and DEL, discuss the outcome of these diseases with current standard as well as promising new approaches and conclude with a section on novel agents that are in development for these diseases.
Asunto(s)
Linfoma/genética , Edad de Inicio , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , Descubrimiento de Drogas , Regulación Neoplásica de la Expresión Génica , Genes myc , Predisposición Genética a la Enfermedad , Humanos , Inmunoterapia , Linfoma/patología , Linfoma/terapia , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Terapia Molecular Dirigida , Mutación , Oncogenes , Fenotipo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Translocación Genética , Resultado del TratamientoRESUMEN
MicroRNA (miRNA), a class of non-protein-coding RNAs, plays a critical role in many cellular processes, such as invasion, proliferation and migration, and also function in disease pathology. The transcription factor and proto-oncogene B cell CLL/lymphoma 6 (BCL6) is aberrantly expressed in various cancers. An increasing body of evidence has demonstrated that miRNAs and BCL6 can target one another and mutually adjust their expression which are of great importance in the pathogenesis of various cancers. In this report, we summarize the mutual interaction between miRNAs and BCL6, which have been studied in cancers, highlighting their mechanisms and potential therapeutic targets in cancers.