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Gene expression changes induced in the stromal cell line EL08-1D2 by co-culture with leukemic B cells (CLL)

ABSTRACT: Tumor cell survival critically depends on heterotypic communication with benign cells in the microenvironment. Here we describe a novel survival signaling pathway activated in stromal cells by contact to B-cells from chronic lymphocytic leukemia (CLL) patients. The expression of PKC-βII and the subsequent activation of NF-κB in bone marrow stromal cells is a prerequisite to support the survival of malignant B-cells. PKC-β knockout mice are insusceptible to CLL-transplantations, underscoring the in vivo significance of the PKC-βII- NF-κB signaling pathway in the tumor microenvironment. Upregulated stromal PKC-βII in biopsies from CLL, breast- and pancreatic- cancer patients suggest that this pathway may commonly be activated in a variety of malignancies. We used microarrays to determine gene expression changes induced by co-culturing with leukemic B-cells (CLL) in EL08-1D2 cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE36414 | GEO | 2013/03/08

SECONDARY ACCESSION(S): PRJNA155537

REPOSITORIES: GEO

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Effect of NF-kappaB activation in bone marrow stromal cells co-cultured with CLL cells

Project description:Tumor cell survival critically depends on heterotypic communication with benign cells in the microenvironment. Here we describe a novel survival signaling pathway activated in stromal cells by contact to B-cells from chronic lymphocytic leukemia (CLL) patients. The expression of PKC-βII and the subsequent activation of NF-κB in bone marrow stromal cells is a prerequisite to support the survival of malignant B-cells. PKC-β knockout mice are insusceptible to CLL-transplantations, underscoring the in vivo significance of the PKC-βII- NF-κB signaling pathway in the tumor microenvironment. Upregulated stromal PKC-βII in biopsies from CLL, breast- and pancreatic- cancer patients suggest that this pathway may commonly be activated in a variety of malignancies. We used microarrays to determine Nemo/ IKK-gamma dependent gene expression changes in bone marrow stromal cells (BMSCs) induced by co-culturing with leukemic B-cells (CLL)

2013-03-08 | GSE36415 | GEO

Gene expression changes induced in the stromal cell line EL08-1D2 by co-culture with leukemic B cells (CLL)

Project description:Tumor cell survival critically depends on heterotypic communication with benign cells in the microenvironment. Here we describe a novel survival signaling pathway activated in stromal cells by contact to B-cells from chronic lymphocytic leukemia (CLL) patients. The expression of PKC-M-NM-2II and the subsequent activation of NF-M-NM-:B in bone marrow stromal cells is a prerequisite to support the survival of malignant B-cells. PKC-M-NM-2 knockout mice are insusceptible to CLL-transplantations, underscoring the in vivo significance of the PKC-M-NM-2II- NF-M-NM-:B signaling pathway in the tumor microenvironment. Upregulated stromal PKC-M-NM-2II in biopsies from CLL, breast- and pancreatic- cancer patients suggest that this pathway may commonly be activated in a variety of malignancies. We used microarrays to determine gene expression changes induced by co-culturing with leukemic B-cells (CLL) in EL08-1D2 cells. We compared EL08-1D2 cells co-cultured for 5 days with leukemic B-cells to EL08-1D2 mono-cultured cells by microarray analysis on Affymetrix MG-430_2.0 arrays.

2013-03-08 | E-GEOD-36414 | biostudies-arrayexpress

Effect of NF-kappaB activation in bone marrow stromal cells co-cultured with CLL cells

Project description:Tumor cell survival critically depends on heterotypic communication with benign cells in the microenvironment. Here we describe a novel survival signaling pathway activated in stromal cells by contact to B-cells from chronic lymphocytic leukemia (CLL) patients. The expression of PKC-M-NM-2II and the subsequent activation of NF-M-NM-:B in bone marrow stromal cells is a prerequisite to support the survival of malignant B-cells. PKC-M-NM-2 knockout mice are insusceptible to CLL-transplantations, underscoring the in vivo significance of the PKC-M-NM-2II- NF-M-NM-:B signaling pathway in the tumor microenvironment. Upregulated stromal PKC-M-NM-2II in biopsies from CLL, breast- and pancreatic- cancer patients suggest that this pathway may commonly be activated in a variety of malignancies. We used microarrays to determine Nemo/ IKK-gamma dependent gene expression changes in bone marrow stromal cells (BMSCs) induced by co-culturing with leukemic B-cells (CLL) We compared mouse BMSC cells from Nemo knockout cells (Nemo+CRE) and Nemo wild type cells (Nemo-CRE) co-cultured for 5 days with leukemic B-cells microarray analysis on Affymetrix MG-430_2.0 arrays..

2013-03-08 | E-GEOD-36415 | biostudies-arrayexpress

Novel spirocyclic dimer, SpiD3, targets critical tumor survival pathways and displays potent preclinical activity in B-cell chronic lymphocytic leukemia

Project description:Chronic lymphocytic leukemia (CLL) cell survival and growth is fueled by aberrant activation of various pro-survival signaling pathways within tumor niches. Specifically, B-cell receptor (BCR) signaling, toll-like receptor signaling, and supportive cellular interactions drive constitutive activation of NF-κB signaling and transcription of proliferative/pro-survival genes. Directly targeting the NF-κB pathway has been a challenge, however, herein, we investigated SpiD3, a spirocyclic dimer and novel NF-κB pathway inhibitor in preclinical models of CLL. Through cross-linking NF-κB proteins, SpiD3 attenuated NF-κB signaling in CLL cells independent of microenvironmental signals. Our integrated multi-omics and functional analyses revealed BCRNF-κB signaling, endoplasmic reticulum stress, oxidative stress, and activation of the unfolded protein response among the top pathways modulated by SpiD3 treatment. This was accompanied by marked inhibition of global protein synthesis, cumulating in profound anti-tumor properties in CLL cells. SpiD3 also modulated tumor microenvironment interactions shown by decreased chemokine and cytokine gene expression as well as decreased CLL chemotaxis towards CXCL-12 and CXCL-13. Moreover, SpiD3 induced apoptosis of stroma-protected primary CLL cells comparable to the BCR-targeting agent, ibrutinib. SpiD3 strikingly demonstrated selective cytotoxicity towards CLL cells compared to healthy lymphocytes, synergized with ibrutinib, and retained its anti-tumor effects in ibrutinib-resistant CLL cells. Altogether, our findings provide preclinical evidence for SpiD3 as an attractive therapeutic agent for CLL, especially in the context of relapsed/refractory disease.

2024-04-26 | GSE236239 | GEO

Notch2 controls non-autonomous Wnt-signalling in chronic lymphocytic leukaemia

Project description:The Wnt-signalling pathway is one of the core de-regulated pathways in chronic lymphocytic leukemia (CLL), activated in a subset of patients by somatic coding mutations. Here we describe an alternative mechanism of Wnt-activation in malignant B cells, mediated by Notch2 activity in mesenchymal stromal cells (MSC) in the tumor microenvironment. We identified that tumor cells specifically induce and activate Notch2 in MSCs. Notch2 orchestrates the expression of target genes essential for the activation of canonical Wnt-signaling in CLL cells. Mechanistically, stromal Notch2 mediates the stabilization of â-catenin by inhibiting the activation of Gsk3-â in malignant B cells. Pharmacological inhibition of the Wnt-pathway mitigates microenvironment-mediated survival of malignant B cells in vitro. Similarly, inhibition of Notch-signaling impaired survival of CLL cells and disease engraftment in a PDX mouse model. Notch2 activation in the tumour microenvironment is a pre-requisite for the GSK3-â dependent activation of the canonical Wnt-signaling in tumor cells.

2018-09-19 | PXD010401 | Pride

Label-Free Quantitative Proteomic Profiling of LAD2 Mast Cell Releasates

Project description:Tween-80 is one of the most important causes resulting in anaphylactoid reaction. However, its mechanism remains unclear. A Label-free LCMS/MS-based proteomics was used to analyze Tween-80-stimulated LAD2 mast cell releasates. Out of a total dataset of 2546 proteins, 882 proteins were found in the supernate samples of Tween-80-treated LAD2 mast cells; 313 proteins were up-expressed and 111 proteins were down-expressed. KEGG pathway analysis showed that endocytosis was the largest class of pathway. A total of 52 proteins were involved in endocytosis, and mainly related to G-protein-coupled receptor (GPCR)-endocytosis and EGFR-endocytosis. Cell adhesion molecules (CAMs) pathway was the most significant differences, with a total of 21 proteins involved. NF-κB signaling activation and calcium signaling pathway play an important role in Tween-80-induced LAD2 cells activation. Proteins, including tyrosine-protein kinase, PLCγ, PKCβ, and p50/p65, were mainly involved in NF-κB pathways. NF-κB signaling activation mainly involved in tyrosine-protein kinase, PLCγ, PKCβ, and NF-κB p50/p65. Calcium signaling pathway mainly related to PLCγ/PKC PLCγ/STIM1 mediated store-operated calcium entry (SOCE) and PLCγ mediated store-operated calcium entry (SOCE)PLCγ/PKC pathway. These results suggest that Tween-80 might be internalized via GPCR-endocytosis, which induces degranulation by SOCE PLCγ/PKC or SOCE PLCγ/PKC pathways mediated calcium influx, and promotes the generation of inflammatory mediators and CAMs via NF-κB signaling pathway finally resulting in anaphylactoid reaction.

2019-11-04 | PXD016123 | iProX

A Retinoic Acid-dependent Stroma-Leukemia Crosstalk Promotes Chronic Lymphocytic Leukemia Progression [RNA-seq]

Project description:In B-cell chronic lymphocytic leukemia (CLL), the non-hematopoietic stromal microenvironment plays a critical role in promoting tumor cell recruitment, activation, survival and expansion. Using the Eμ-TCL1 mouse model, we demonstrate that leukemic cells induce the activation of retinoid acid synthesis and signaling in stromal cells of the lymphoid microenvironment.

2018-05-09 | GSE111612 | GEO

A Retinoic Acid-dependent Stroma-Leukemia Crosstalk Promotes Chronic Lymphocytic Leukemia Progression [microarray]

2018-05-09 | GSE111470 | GEO

MALT1 Inhibition Is Efficacious in Both Naïve and Ibrutinib-Resistant Chronic Lymphocytic Leukemia.

Project description:The clinical efficacy displayed by ibrutinib in chronic lymphocytic leukemia (CLL) has been challenged by the frequent emergence of resistant clones. The ibrutinib target, Bruton's tyrosine kinase (BTK), is essential for B-cell receptor signaling, and most resistant cases carry mutations in BTK or PLCG2, a downstream effector target of BTK. Recent findings show that MI-2, a small molecule inhibitor of the para-caspase MALT1, is effective in preclinical models of another type of BCR pathway-dependent lymphoma. We therefore studied the activity of MI-2 against CLL and ibrutinib-resistant CLL. Treatment of CLL cells in vitro with MI-2 inhibited MALT1 proteolytic activity reduced BCR and NF-κB signaling, inhibited nuclear translocation of RelB and p50, and decreased Bcl-xL levels. MI-2 selectively induced dose and time-dependent apoptosis in CLL cells, sparing normal B lymphocytes. Furthermore, MI-2 abrogated survival signals provided by stromal cells and BCR cross-linking and was effective against CLL cells harboring features associated with poor outcomes, including 17p deletion and unmutated IGHV Notably, MI-2 was effective against CLL cells collected from patients harboring mutations conferring resistance to ibrutinib. Overall, our findings provide a preclinical rationale for the clinical development of MALT1 inhibitors in CLL, in particular for ibrutinib-resistant forms of this disease. Cancer Res; 77(24); 7038-48. ©2017 AACR.

2018-04-03 | GSE98206 | GEO

Expression of ZAP70 in CLL activates NF-κB signalling

Project description:Chronic lymphocytic leukemia (CLL) is a disease with a highly variable prognosis. The clinical course can however be predicted thanks to prognostic markers. Poor prognosis is associated with expression of a B cell receptor (BCR) from unmutated immunoglobulin variable heavy-chain genes (IgVH) and expression of zeta associated protein of 70 kDa (ZAP-70). The reason why ZAP-70 expression is associated with poor prognosis and whether the protein has a direct pathogenic function is at present unknown. By transfer of ZAP-70 to CLL cells, we show here that expression of ZAP-70 in CLL cells leads to increased expression of the NF-κB target genes interleukin-1β (IL-1β), IL-6 and IL-8 upon BCR triggering. This could be blocked by inhibition of NF-κB signaling through inhibition of IκB kinases (IKK). Transcriptome analysis identified a NF-κB RelA signature imposed by ZAP-70 expression in BCR stimulated CLL cells. We conclude that ZAP-70 acts directly as an amplifier of NF-κB signaling in CLL cells which could be an underlying mechanism for its association with poor prognosis and which may represent a therapeutic target.

2013-10-22 | GSE51286 | GEO

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