RESUMEN
Innovative materials for phosphor-converted white light-emitting diodes (pc-LEDs) are much sought after due to the huge potential of the LED technology to reduce energy consumption worldwide. One of the main levers for further improvements are the conversion phosphors. The system Ca1-x Srx AlSiN3 :Eu2+ currently provides one of the most important red-emitting phosphors for pc-LEDs. We report the discovery of the new polymorph ß-Ca1-x Srx AlSiN3 :Eu2+ which allows for significant improvements to LED efficacies. It crystallizes in the orthorhombic space group Pbcn with lattice parameters a=982.43(10)â pm, b=575.2(1)â pm and c=516.12(5)â pm. Compared to α-Ca1-x Srx AlSiN3 :Eu2+ , its emission shows a significantly reduced spectral full-width at half maximum (FWHM). With that, we demonstrated 3 % efficacy increase for white light-emitting pc-LEDs. The new polymorph can easily be industrialised, because the synthesis works on the same equipment as α-Ca1-x Srx AlSiN3 :Eu2+ .
RESUMEN
Transcription factor AP-1 is constitutively activated and IRF4 drives growth and survival in ALK+ and ALK- anaplastic large cell lymphoma (ALCL). Here we demonstrate high-level BATF and BATF3 expression in ALCL. Both BATFs bind classical AP-1 motifs and interact with in ALCL deregulated AP-1 factors. Together with IRF4, they co-occupy AP-1-IRF composite elements, differentiating ALCL from non-ALCL. Gene-specific inactivation of BATFs, or global AP-1 inhibition results in ALCL growth retardation and/or cell death in vitro and in vivo. Furthermore, the AP-1-BATF module establishes TH17/group 3 innate lymphoid cells (ILC3)-associated gene expression in ALCL cells, including marker genes such as AHR, IL17F, IL22, IL26, IL23R and RORγt. Elevated IL-17A and IL-17F levels were detected in a subset of children and adolescents with ALK+ ALCL. Furthermore, a comprehensive analysis of primary lymphoma data confirms TH17-, and in particular ILC3-skewing in ALCL compared with PTCL. Finally, pharmacological inhibition of RORC as single treatment leads to cell death in ALCL cell lines and, in combination with the ALK inhibitor crizotinib, enforces death induction in ALK+ ALCL. Our data highlight the crucial role of AP-1/BATFs in ALCL and lead to the concept that some ALCL might originate from ILC3.
Asunto(s)
Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Linfoma Anaplásico de Células Grandes/etiología , Linfoma Anaplásico de Células Grandes/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Factor de Transcripción AP-1/metabolismo , Sitios de Unión , Sistemas CRISPR-Cas , Proteínas Portadoras/metabolismo , Muerte Celular/genética , Línea Celular Tumoral , Supervivencia Celular , Citocinas/metabolismo , Edición Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Técnicas de Silenciamiento del Gen , Humanos , Linfoma Anaplásico de Células Grandes/patología , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacología , ARN Interferente Pequeño/genética , TranscriptomaRESUMEN
Deregulated transcription factor (TF) activities are commonly observed in hematopoietic malignancies. Understanding tumorigenesis therefore requires determining the function and hierarchical role of individual TFs. To identify TFs central to lymphomagenesis, we identified lymphoma type-specific accessible chromatin by global mapping of DNaseI hypersensitive sites and analyzed enriched TF-binding motifs in these regions. Applying this unbiased approach to classical Hodgkin lymphoma (HL), a common B-cell-derived lymphoma with a complex pattern of deregulated TFs, we discovered interferon regulatory factor (IRF) sites among the top enriched motifs. High-level expression of the proinflammatory TF IRF5 was specific to HL cells and crucial for their survival. Furthermore, IRF5 initiated a regulatory cascade in human non-Hodgkin B-cell lines and primary murine B cells by inducing the TF AP-1 and cooperating with NF-κB to activate essential characteristic features of HL. Our strategy efficiently identified a lymphoma type-specific key regulator and uncovered a tumor promoting role of IRF5.
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Cromatina/metabolismo , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/metabolismo , Factores Reguladores del Interferón/metabolismo , Factor de Transcripción AP-1/metabolismo , Secuencias de Aminoácidos , Animales , Linfocitos B/citología , Línea Celular Tumoral , Linaje de la Célula , Quimiocinas/metabolismo , Quimiotaxis , Citocinas/metabolismo , Desoxirribonucleasa I/metabolismo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Inflamación , Leucocitos Mononucleares/citología , Linfoma/metabolismo , Linfoma no Hodgkin/metabolismo , Ratones , FN-kappa B/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Plásmidos/metabolismo , Bazo/citologíaRESUMEN
B cell differentiation is controlled by a complex network of lineage-restricted transcription factors. How perturbations to this network alter B cell fate remains poorly understood. Here we show that classical Hodgkin lymphoma tumor cells, which originate from mature B cells, have lost the B cell phenotype as a result of aberrant expression of transcriptional regulators. The B cell-specific transcription factor program was disrupted by overexpression of the helix-loop-helix proteins ABF-1 and Id2. Both factors antagonized the function of the B cell-determining transcription factor E2A. As a result, expression of genes specific to B cells was lost and expression of genes not normally associated with the B lineage was upregulated. These data demonstrate the plasticity of mature human lymphoid cells and offer an explanation for the unique classical Hodgkin lymphoma phenotype.
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Linfocitos B/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/antagonistas & inhibidores , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Enfermedad de Hodgkin/metabolismo , Proteína 2 Inhibidora de la Diferenciación/metabolismo , Linfocitos B/inmunología , Linfocitos B/patología , Secuencia de Bases , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Línea Celular Tumoral , Dimerización , Expresión Génica , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/inmunología , Enfermedad de Hodgkin/patología , Humanos , Proteína 2 Inhibidora de la Diferenciación/genética , Complejos Multiproteicos , Factor de Transcripción PAX5/genética , Factor de Transcripción PAX5/metabolismo , Fenotipo , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismoRESUMEN
Transcription factor nuclear factor kappa B (NF-kappaB) plays a central role in the pathogenesis of classical Hodgkin lymphoma (cHL). In anaplastic large-cell lymphomas (ALCLs), which share molecular lesions with cHL, the NF-kappaB system has not been equivalently investigated. Here we describe constitutive NF-kappaB p50 homodimer [(p50)2] activity in ALCL cells in the absence of constitutive activation of the IkappaB kinase (IKK) complex. Furthermore, (p50)2 contributes to the NF-kappaB activity in Hodgkin/Reed-Sternberg (HRS) cells. Bcl-3, which is an inducer of nuclear (p50)2 and is associated with (p50)2 in ALCL and HRS cell lines, is abundantly expressed in ALCL and HRS cells. Notably, a selective overexpression of Bcl-3 target genes is found in ALCL cells. By immunohistochemical screening of 288 lymphoma cases, a strong Bcl-3 expression in cHL and in peripheral T-cell non-Hodgkin lymphoma (T-NHL) including ALCL was found. In 3 of 6 HRS cell lines and 25% of primary ALCL, a copy number increase of the BCL3 gene locus was identified. Together, these data suggest that elevated Bcl-3 expression has an important function in cHL and peripheral T-NHL, in particular ALCL.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/metabolismo , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/metabolismo , Subunidad p50 de NF-kappa B/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas del Linfoma 3 de Células B , Línea Celular , Dimerización , Humanos , Proteínas I-kappa B/metabolismo , Interleucina-9/metabolismo , Linfoma de Células T Periférico/patología , Análisis por Micromatrices , Proteínas Oncogénicas v-rel/metabolismo , Unión Proteica , Proteínas Proto-Oncogénicas/genética , Factores de TranscripciónRESUMEN
Resistance to death receptor-mediated apoptosis is supposed to be important for the deregulated growth of B cell lymphoma. Hodgkin/Reed-Sternberg (HRS) cells, the malignant cells of classical Hodgkin's lymphoma (cHL), resist CD95-induced apoptosis. Therefore, we analyzed death receptor signaling, in particular the CD95 pathway, in these cells. High level CD95 expression allowed a rapid formation of the death-inducing signaling complex (DISC) containing Fas-associated death domain-containing protein (FADD), caspase-8, caspase-10, and most importantly, cellular FADD-like interleukin 1beta-converting enzyme-inhibitory protein (c-FLIP). The immunohistochemical analysis of the DISC members revealed a strong expression of CD95 and c-FLIP overexpression in 55 out of 59 cases of cHL. FADD overexpression was detectable in several cases. Triggering of the CD95 pathway in HRS cells is indicated by the presence of CD95L in cells surrounding them as well as confocal microscopy showing c-FLIP predominantly localized at the cell membrane. Elevated c-FLIP expression in HRS cells depends on nuclear factor (NF)-kappaB. Despite expression of other NF-kappaB-dependent antiapoptotic proteins, the selective down-regulation of c-FLIP by small interfering RNA oligoribonucleotides was sufficient to sensitize HRS cells to CD95 and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Therefore, c-FLIP is a key regulator of death receptor resistance in HRS cells.