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Selective Targeting of the Proliferating Compartment in Chronic Lymhocytic Leukemia by Inhibition or Downregulation of Aurora Kinases

ABSTRACT: Chronic lymphocytic leukemia (CLL) B-cells receive signals from the lymph node and bone marrow (BM) microenvironments that regulate their survival and proliferation. These signals and the pathways that propagate them to the interior of the cell represent potential targets for therapeutic intervention. To characterize the pathways that are activated by the BM microenvironment in CLL cells in vivo, we performed gene expression profiling of tumor cells purified from BM and peripheral blood. Functional classification analysis revealed that the most frequently upregulated genes in BM-CLL cells are genes involved in cell cycle and mitosis. Among the most significantly overexpressed were the Aurora A and B kinases. To investigate whether these kinases could represent potential therapeutic targets in CLL, we performed RNA interference experiments in the CLL cell lines MEC1 and EHEB. Downregulation of Aurora A and B inhibited the proliferation and induced apoptosis in these cells. Similar effects were observed with the pan-Aurora kinase inhibitor VX-680 in primary CLL cells induced to proliferate by CpG-ODN and IL-2. VX-680 also inhibited leukemia growth in vivo in a mouse model of CLL. These data suggest that inhibition of Aurora kinases could represent a potential strategy to selectively target the proliferating compartment in CLL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE30896 | GEO | 2011/07/26

SECONDARY ACCESSION(S): PRJNA144237

REPOSITORIES: GEO

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Selective Targeting of the Proliferating Compartment in Chronic Lymhocytic Leukemia by Inhibition or Downregulation of Aurora Kinases

Project description:Chronic lymphocytic leukemia (CLL) B-cells receive signals from the lymph node and bone marrow (BM) microenvironments that regulate their survival and proliferation. These signals and the pathways that propagate them to the interior of the cell represent potential targets for therapeutic intervention. To characterize the pathways that are activated by the BM microenvironment in CLL cells in vivo, we performed gene expression profiling of tumor cells purified from BM and peripheral blood. Functional classification analysis revealed that the most frequently upregulated genes in BM-CLL cells are genes involved in cell cycle and mitosis. Among the most significantly overexpressed were the Aurora A and B kinases. To investigate whether these kinases could represent potential therapeutic targets in CLL, we performed RNA interference experiments in the CLL cell lines MEC1 and EHEB. Downregulation of Aurora A and B inhibited the proliferation and induced apoptosis in these cells. Similar effects were observed with the pan-Aurora kinase inhibitor VX-680 in primary CLL cells induced to proliferate by CpG-ODN and IL-2. VX-680 also inhibited leukemia growth in vivo in a mouse model of CLL. These data suggest that inhibition of Aurora kinases could represent a potential strategy to selectively target the proliferating compartment in CLL. To identify gene expression related to microenvironmental stimuli in B-cell Chronic Lymphocytic Leukemia (CLL) cells in vivo, expression profiles of CLL cells purified (>95%) from bone marrow (BM) and peripheral blood (PB) were compared. Paired BM and PB samples from 6 individuals were used for this analysis.

2011-07-25 | E-GEOD-30896 | biostudies-arrayexpress

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2023-09-14 | PXD033239 | Pride

Extracellular vesicle role in Chronic Lymphocytic Leukemia B-cells defined by microarray analysis

Project description:Interactions between Chronic Lymphocytic Leukemia B-cells (CLL B-cells) and the microenvironment (ME) play a major function in the physiopathology of CLL. Extracellular vesicles (EVs) (composed of exosomes and microparticles) have been shown to play an important role in cell communication. EVs, purified by ultracentrifugation from bone marrow mesenchymal stromal cells (BM-MSC) culture, were added to CLL B-cells. Microarray study highlighted 805 differentially expressed genes between CLL-B-cells cultured with and without EVs. Of these, CCL3/4, EGR1/2/3, MYC (involved in BCR pathway) were increased while pro-apoptotic genes like HRK were decreased. We showed for the first time the potential of EVs alone to induce gene expression modifications in CLL B-cell, notably in BCR and apoptosis pathways. We concluded that a substantial part of communication between CLL B-cells and BM-ME is mediated through EV.

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Project description:From RNAseq analysis of 53 esLUAD, we identified a gene signature distinguishing invasive and indolent tumors. Regulatory network analysis identified aurora kinases as master regulators of the gene signature. So we applied an aurora kinase pan inhibitor, AMG900, using A549 and H1792 cells to confirm whether the expression of pro-invasive genes were impacted by aurora kinase activity suppression.

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The investigational Aurora kinase A inhibitor MLN8237 induces defects in cell viability and cell cycle progression in mouse bladder cancer cells in vitro and in vivo

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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.

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Simultaneous silencing of Aurora-A and UHRF1 inhibits colorectal cancer cell growth by regulating the expression of DNMT1 and STAT1

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Expression of ZAP-70 in CLL activates NF-M-NM-:B signaling

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-M-NM-:B target genes interleukin-1M-NM-2 (IL-1M-NM-2), IL-6 and IL-8 upon BCR triggering. This could be blocked by inhibition of NF-M-NM-:B signaling through inhibition of IM-NM-:B kinases (IKK). Transcriptome analysis identified a NF-M-NM-:B RelA signature imposed by ZAP-70 expression in BCR stimulated CLL cells. We conclude that ZAP-70 acts directly as an amplifier of NF-M-NM-:B signaling in CLL cells which could be an underlying mechanism for its association with poor prognosis and which may represent a therapeutic target. 22 patient samples, Stimulated for 3h or 24h, Electroporated with capped ZAP-70 mRNA or uncapped ZAP-70 mRNA (negative control)

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