Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA204235 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:In the activated B-cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), the most frequent gain-of-function mutations target MyD88, a signaling adapter for Tolllike receptors (TLRs). The most prevalent oncogenic mutant, MyD88 L265P, occurs in 29% of cases and is the most active in engaging the NF-kappaB pathway. Here we show that MyD88 mutants do not function autonomously, but rather require TLR7, TLR9, and to a lesser extent, TLR4 to promote the survival of ABC DLBCL cells. Unlike wild type MyD88, MyD88 mutants associate constitutively with TLR7 and TLR9 in ABC DLBCL cells. Like ligand-induced TLR7/9 signaling in normal immune cells, the survival of ABC DLBCL cell lines depends upon translocation of TLR7 and TLR9 to acidic endolysosomes, where proteolytic processing of their ligand binding ectodomains is required for their oncogenic signaling. ABC DLBCL viability also depends upon CD14, a co-receptor for TLR7 and TLR9 that promotes engagement of nucleic acid ligands by these receptors. Point mutations in the TLR7 or TLR9 ectodomains that abrogate ligand binding and/or signaling were incapable of sustaining ABC DLBCL survival. An inhibitory oligonucleotide that suppresses TLR9 responses in normal B cells blocked NF-kappaB signaling and survival of ABC DLBCL lines. Together, these data suggest that an endogenous TLR ligand may play a pathogenic role in ABC DLBCL and provide a rationale for targeting TLR signaling to improve therapy of this aggressive lymphoma. Gene expression was analyzed using Agilent human 2-color 4X44K oligo gene expression arrays. Cell line, TMD8 ABC-DLBCL, was infected with control (shControl, Cy3), shLTR7 (Cy5) or shLTR9 (Cy5) and changes in gene expression were monitored on day 1 and day 2 after induction of the shRNA with doxycycline, co-hybridizing control and experimental samples (Cy3+Cy5), for a total of 4 arrays.
2014-05-21 | E-GEOD-47147 | biostudies-arrayexpress
Project description:In the activated B-cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), the most frequent gain-of-function mutations target MyD88, a signaling adapter for Tolllike receptors (TLRs). The most prevalent oncogenic mutant, MyD88 L265P, occurs in 29% of cases and is the most active in engaging the NF-kappaB pathway. Here we show that MyD88 mutants do not function autonomously, but rather require TLR7, TLR9, and to a lesser extent, TLR4 to promote the survival of ABC DLBCL cells. Unlike wild type MyD88, MyD88 mutants associate constitutively with TLR7 and TLR9 in ABC DLBCL cells. Like ligand-induced TLR7/9 signaling in normal immune cells, the survival of ABC DLBCL cell lines depends upon translocation of TLR7 and TLR9 to acidic endolysosomes, where proteolytic processing of their ligand binding ectodomains is required for their oncogenic signaling. ABC DLBCL viability also depends upon CD14, a co-receptor for TLR7 and TLR9 that promotes engagement of nucleic acid ligands by these receptors. Point mutations in the TLR7 or TLR9 ectodomains that abrogate ligand binding and/or signaling were incapable of sustaining ABC DLBCL survival. An inhibitory oligonucleotide that suppresses TLR9 responses in normal B cells blocked NF-kappaB signaling and survival of ABC DLBCL lines. Together, these data suggest that an endogenous TLR ligand may play a pathogenic role in ABC DLBCL and provide a rationale for targeting TLR signaling to improve therapy of this aggressive lymphoma.
2014-05-21 | GSE47147 | GEO
Project description:Several Toll-like receptors are activated by Listeria monocytogenes infection, resulting in the activation of MyD88 dependent signaling pathway. However, the negative role of MyD88 in gene expresson is unclear. To address this, we performed microarray analysis of mRNAs from WT or MyD88-/- peritoneal macrophages infected with Listeria monocytogenes.
2014-06-29 | GSE52115 | GEO
Project description:Constitutively active RAS plays a central role in the development of skin cancer in the classical two stage skin carcinogenesis in mice and in a number of human cancers. Ras-mediated tumor formation is commonly associated with upregulation of cytokines and chemokines that mediate an inflammatory response considered relevant to oncogenesis. MyD88 is a crucial intermediate in the expression of multiple innate immune responders through signaling from the Toll-like/IL-1R family. We report that mice ablated for MyD88 or the IL-1R are resistant to topical skin carcinogenesis, and cultured MyD88-/- keratinocytes transduced with an oncogenic ras vector form only a few small tumors in orthotopic grafts. Initiated keratinocytes arising from oncogenic activation of ras are hyperproliferative but also resist signals for induced differentiation and upregulate a host of pro-inflammatory genes. Ras-transduced MyD88-/- keratinocytes are also hyperproliferative but the differentiation response is intact and pro-inflammatory genes are not upregulated. Using both genetic and pharmacological approaches, we find that in keratinocytes, the differentiation and immune regulation functions mediated by oncogenic ras require the establishment of an autocrine loop through IL-1α and its receptor leading to NF-κB activation. In the absence of MyD88 or IL-1R, this loop cannot be established. Further, blocking the IL-1a mediated NF-κB activation in ras-transduced wildtype keratinocytes corrects the defect in both differentiation response and proinflammatory gene expression. Collectively, these results demonstrate that ras activation converts normal keratinocytes to an initiated phenotype through a series of potentially reversible feedback signals that provide therapeutic opportunities through inhibition of IL-1 signaling. Gene expression comparison of wild type ras-transformed keratinocytes untreated (n=3) or treated (n=3) in vitro with the IL1R antagonist Anakinra.
2011-08-28 | E-GEOD-22777 | biostudies-arrayexpress
Project description: Not available
| S-EPMC2531291 | biostudies-literature
Project description:RNA extracted at 240min. Samples are rRNA depleted. Expression measurement of Homo sapiens genes.
2019-07-31 | GSE114179 | GEO
Project description:Most autoreactive B cells are normally counterselected during early B cell development. To determine whether Toll-like receptors (TLRs) regulate the removal of autoreactive B lymphocytes, we tested the reactivity of recombinant antibodies from single B cells isolated from patients deficient for IL-1R-associated kinase (IRAK)-4, myeloid differentiation factor 88 (MyD88) and UNC-93B. Indeed, all TLRs except TLR3 require IRAK-4 and MyD88 to signal and UNC-93B-deficient cells are unresponsive to TLR3, TLR7, TLR8 and TLR9. All patients suffered from defective central and peripheral B cell tolerance checkpoints resulting in the accumulation of large numbers of autoreactive mature naïve B cells in their blood. Hence, TLR7, TLR8, and TLR9 may prevent the recruitment of developing autoreactive B cells in healthy donors. Paradoxically, IRAK-4-, MyD88- and UNC-93B-deficient patients did not display autoreactive antibodies in their serum nor developed autoimmune diseases, suggesting that IRAK-4, MyD88 and UNC-93B pathway blockade may thwart autoimmunity in humans.
2008-10-23 | GSE13300 | GEO
Project description:Plasmacytoid dendritic cells (pDC) are the major source of type I IFN (IFN-I) in vivo during Murine Cytomegalovirus (MCMV) infection. This response requires pDC-intrinsic MyD88-dependent signaling by Toll Like Receptors 7/9. Provided that they express appropriate recognition receptors such as Ly49H, Natural Killer (NK) cells can directly sense and kill MCMV-infected cells. While MyD88- and Ly49H-dependent responses can contribute to MCMV control, the objective is to understand the relative importance of these 3 mechanisms. In order to decipher the relative impact of MyD88- and Ly49H-dependent mechanisms during MCMV infection, we performed a genome-wide expression analysis on total spleen of Ly49H-/-MyD88+/+, Ly49H-/-MyD88-/-, Ly49H+/+MyD88+/+ and Ly49H+/+MyD88-/- BALB/c mice at different time points after MCMV infection (d0, d1,5, d2, d3 and d6).
2015-04-24 | GSE62729 | GEO
Project description:HIV-1 Activates Macrophages Independent of Toll-like Receptors
| PRJNA109751 | ENA