Mouse cancer cells and bone-marrow macrophages expressing or silenced for IKKA and IKKB
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA541084 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:A subtype of diffuse large B-cell lymphoma (DLBCL), termed activated B-cell-like (ABC) DLBCL, depends on constitutive NF-kB pathway signaling for survival. Small molecule inhibitors of IkB kinase b (IKKb), a key regulator of the NF-kB pathway, kill ABC DLBCL cells and hold promise for the treatment of this lymphoma type. We conducted an RNA interference genetic screen to investigate potential mechanisms of resistance of ABC DLBCL cells to IKKb inhibitors. We screened a library of small hairpin RNAs (shRNAs) targeting 500 protein kinases for shRNAs that would kill an ABC DLBCL cell line in the presence of a small molecule IKKb inhibitor more effectively than in its absence. Two independent shRNAs targeting IKKa synergized with the IKKb inhibitor to kill three different ABC DLBCL cell lines but were not toxic by themselves. Surprisingly, IKKa shRNAs blocked the classical rather than the alternative NF-kB pathway in ABC DLBCL cells, as judged by inhibition of IkBa phosphorylation. IKKa shRNA toxicity was reversed by coexpression of wild type but not kinase inactive forms of IKKa, suggesting that IKKa may directly phosphorylate IkBa under conditions of IKKb inhibition. These results suggest that therapy for ABC DLBCL may be improved by targeting both IKKa and IKKb. Keywords: compound treatment design Gene expression profiling of OCI-Ly3 cells with or without expressing IKKa shRNA in the presence or absence of 12.5 uM IKKb inhibitor for 2 and 3 days. Four samples were analyzed.
2009-06-01 | E-GEOD-11902 | biostudies-arrayexpress
Project description:A subtype of diffuse large B-cell lymphoma (DLBCL), termed activated B-cell-like (ABC) DLBCL, depends on constitutive NF-kB pathway signaling for survival. Small molecule inhibitors of IkB kinase b (IKKb), a key regulator of the NF-kB pathway, kill ABC DLBCL cells and hold promise for the treatment of this lymphoma type. We conducted an RNA interference genetic screen to investigate potential mechanisms of resistance of ABC DLBCL cells to IKKb inhibitors. We screened a library of small hairpin RNAs (shRNAs) targeting 500 protein kinases for shRNAs that would kill an ABC DLBCL cell line in the presence of a small molecule IKKb inhibitor more effectively than in its absence. Two independent shRNAs targeting IKKa synergized with the IKKb inhibitor to kill three different ABC DLBCL cell lines but were not toxic by themselves. Surprisingly, IKKa shRNAs blocked the classical rather than the alternative NF-kB pathway in ABC DLBCL cells, as judged by inhibition of IkBa phosphorylation. IKKa shRNA toxicity was reversed by coexpression of wild type but not kinase inactive forms of IKKa, suggesting that IKKa may directly phosphorylate IkBa under conditions of IKKb inhibition. These results suggest that therapy for ABC DLBCL may be improved by targeting both IKKa and IKKb. Keywords: compound treatment design
2009-06-01 | GSE11902 | GEO
Project description:Gene expressions of wild-type, IKKa-/- and IKKa+/+ reconstituted MEFs were compared Keywords: Gene Knockout and reconstituted
2008-02-06 | GSE6986 | GEO
Project description:In this study we used bioluminescent reporter mice to discover that transplantable tumors cause nuclear factor-kappa B activation in host macrophages. This effect is mostly aggravated in mouse models of malignant pleural effusion, is dependent on KRAS mutation status of tumor cells, and is delivered via secretory versican, a toll-like receptor 2 ligand. Versican, in turn activates nuclear factor-kappa B in host macrophages via the canonical inhibitor of nuclear factor-kappa B kinase beta (IKKbeta), resulting in release of myeloid-secreted interleukin-1beta in the tumor microenvironment. Silencing of versican in cancer cells or conditional deletion of IKKbeta in macrophages abrogates myeloid nuclear factor-kappa B activation as well as tumor progression.
2025-05-02 | GSE130716 | GEO
Project description:Multiple transcription factors regulate B cell commitment, which coordinates with myeloid–erythroid lineage differentiation. One such factor, NF-kB, has long been speculated to regulate early B cell development; however, this issue remains controversial. IKKa is required for splenic B cell maturation, but not for bone marrow (BM) B cell development. Here, we unexpectedly found defective BM B cell development and an increased myeloid–erythroid lineages in kinase-dead IKKa (KA/KA) knock-in mice. Markedly increased cytosolic p100, an NF-kB2 inhibitory form, and reduced nuclear NF-kB p65, RelB, p50, and p52, as well as IKKa, was observed in KA/KA splenic and BM B cells. Several B- and myeloid–erythroid-cell regulators, including Pax5, were deregulated in KA/KA BM B cells. Using fetal liver and BM congenic transplants, and IKKa deletion from early hematopoietic cells in mice, this defect was identified as B cell intrinsic and as an early event during hematopoiesis. Re-expression of IKKa, Pax5, or combined NF-kB molecules promoted B cell development, but repressed myeloid–erythroid cell differentiation in KA/KA BM B cells. Together, these results demonstrate that IKKa regulates B-lineage commitment via combined canonical and noncanonical NF-kB transcriptional activity to target Pax5 expression during hematopoiesis.
2011-07-02 | GSE30363 | GEO
Project description:Bone marrow endosteum houses Hedgehog-susceptible Dlx5-expressing osteoblast precursor cells
| PRJNA1177850 | ENA
Project description:RATIONALE: Radiation therapy uses high-energy x-rays to damage cancer cells. Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Combining chemotherapy with bone marrow transplantation may allow the doctor to give higher doses of chemotherapy drugs and kill more tumor cells.
PURPOSE: Phase II trial to study the effectiveness of bone marrow transplantation in treating patients who have hematologic cancer.
| 2004880 | ecrin-mdr-crc
Project description:Local renin antiotensin systems have been identified for many extra-renal sites. Bone marrow has been proposed as one such site, although the nature of the renin-expressing cell type(s) has not been established. Affymetrix microarrays were used to characterize the expression profile of renin-expressing GFP positive cells. Green fluorescent protein positive cells were sorted from whole bone marrow collected from adult transgenic mice. Bone marrow from several mice was collected and pooled on the day of a FACS sort. A portion of this was reserved for RNA extraction while the remainder was sorted. RNA was prepared with Trizol. Bone marrow collection and sorting was performed 3 times so that microarrays could be run in triplicate.
2014-02-17 | E-GEOD-53916 | biostudies-arrayexpress
Project description:We have previously shown that IKKa coordinates the activation of several oncogenic and therapy-resistant pathways, including ATM/DDR, BRD4, and JAK/STAT3, independently of canonical NF-kB signaling. Here, we found that IKKa suppression, either genetically or pharmacologically, led to stabilization of ZO-1 protein and increased CLDN2 expression, resulting in altered tight junction distribution. IKKa KO cells showed a shift in their migratory mode towards collective migration, which is associated with superior metastatic capacity in vivo. Analysis of single-cell (sc)RNA-seq data from a mouse model of CRC revealed an accumulation of the tight junction signature, including ZO-1 and CLND2, in the metastatic populations. scRNA-seq analysis of patient-derived organoid (PDO5) identified three distinct epithelial cell clusters (C2, C4 and C8) that show a significant enrichment for the metastasis-specific EpiHR signature and the tight junction signature. In particular, C2 and C8 display unique genetic signatures that are significantly upregulated in IKKa KO cells and enriched in the PDO5 IKKa KO-derived metastases. Analysis of human paraffin-embedded CRC specimens led to the identification of vascular tumor infiltrates with ZO-1 and CLDN2-positive cluster-like or glandular phenotypes. The concomitant presence of low CHUCK (IKKa) and high TJP1 (ZO-1) RNA levels is sufficient to predict poor prognosis in CRC patients. These results suggest that the presence of collectively migrating cancer cells in the vascular infiltrates, characterized by high levels of tight junction proteins, could be standardized as a prognostic tool to predict metastasis. We anticipate the use of drugs targeting tight junction elements for metastasis prevention.
2025-12-02 | GSE274321 | GEO
Project description:Bone marrow endosteum houses Hedgehog-susceptible Dlx5-expressing osteoblast precursor cells [Fgfr3CE_Cxcl12GFP]
| PRJNA1179926 | ENA