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A core proliferative program induced by B-cell receptor stimulation in chronic lymphocytic leukemia cells

ABSTRACT: The B-cell receptor (BCR) signaling is crucial for the pathophysiology of chronic lymphocytic leukemia (CLL). Although the BCR has recently emerged as a new therapeutic target the precise mechanisms by which BCR signaling controls neoplastic B-cell proliferation are still ill characterized. Here, by comparing proliferating vs. non-proliferating cells from aggressive CLL patients, we longitudinally characterized the transcriptional and proteomic response of CLL cells after BCR engagement ex vivo. Of the 5,733 genes and/or proteins which expression was modulated after BCR activation, we identified a CLL proliferative signature including 430 genes and 374 proteins. Mathematical modelling of this signature revealed a nested sub-regulatory network comprising transcription factors activated within hours after cell activation linked to proteins involved in cell proliferation days after stimulation. The mining of this core cellular program sustaining primary human cancer cells proliferation provides an evidence based-resource for innovative therapeutic perspectives.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Cell, Cell Culture

SUBMITTER: Leslie MULLER

LAB HEAD: Sarah CIANFERANI

PROVIDER: PXD013573 | Pride | 2021-03-29

REPOSITORIES: Pride

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A core proliferative program induced by B-cell receptor stimulation in chronic lymphocytic leukemia cells

Project description:The B-cell receptor (BCR) signaling is crucial for the pathophysiology of chronic lymphocytic leukemia (CLL). Although the BCR has recently emerged as a new therapeutic target the precise mechanisms by which BCR signaling controls neoplastic B-cell proliferation are still ill characterized. Here, by comparing proliferating vs. non-proliferating cells from aggressive CLL patients, we longitudinally characterized the transcriptional and proteomic response of CLL cells after BCR engagement ex vivo. Of the 5,733 genes and/or proteins which expression was modulated after BCR activation, we identified a CLL proliferative signature including 430 genes and 374 proteins. Mathematical modelling of this signature revealed a nested sub-regulatory network comprising transcription factors activated within hours after cell activation linked to proteins involved in cell proliferation days after stimulation. The mining of this core cellular program sustaining primary human cancer cells proliferation provides an evidence based-resource for innovative therapeutic perspectives.

2021-09-08 | PXD013696 | Pride

Temporal transcriptional response from primary human chronic lymphocytic leukemia (CLL)-cells after B-cell receptor stimulation.

Project description:The B-cell receptor (BCR) signaling is crucial for the pathophysiology of most leukemias and lymphomas originated from mature B lymphocytes and has emerged as a new therapeutic target, especially for chronic lymphocytic leukemia (CLL). However, the precise mechanisms by which BCR signaling controls neoplastic B-cell proliferation are ill characterized. This work was performed using primary leukemic cells of untreated patients at initial stage of CLL (Binet stage A / Rai 0) presenting biological characteristics of aggressive form of the disease (unmutated IGHV genes and ZAP70 protein expression). In order to mimic the primary leukemogenic step occurring in vivo, this study focused on the BCR-dependent proliferation of CLL cells induced ex vivo using anti-IgM, together with mandatory co-stimulating factors (CD40L, IL-4 and IL-21) (Schleiss, Sci Rep, 2019). Cell proliferation was objectivized by the emergence of proliferative clusters and the presence of more than 25% of CLL cells that did undergo division within the cell culture at day 6. To capture the specific actors of the proliferative response in these samples, we also included non-proliferating control CLL samples. Gene expression was analyzed by RNA-seq before stimulation (T0) and at the time points 1h, 1h30, 3h30, 6h30, 12h, 24h, 48h and 96h after cell stimulation (n=54 data points), the latest time points corresponding to the emergence of the proliferation clusters.

2021-05-12 | GSE130385 | GEO

RNA-Seq of primary chronic lymphocytic leukaemia (CLL) tumours treated with anti-IgM antibodies against isotype control treated tumours

Project description:Chronic lymphocytic leukemia (CLL) is a highly heterogenous disease, with vastly diverse phenotypes that cause differing clinical courses ranging from benign disease (requiring no treatment), to a rapidly progressive disease and may require aggressive treatment therapy. Key to the B cell is the B-cell receptor (BCR); CLL utilises the BCR to evade apoptosis and promote proliferation and drug resistance through cross-talk between the TME and through BCR activation. Our experiments engage the BCR to determine downstream impact of BCR stimulation on gene expression in CLL (6 hours after stimulation).

2023-05-01 | E-MTAB-12055 | biostudies-arrayexpress

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)

2013-10-22 | E-GEOD-51286 | biostudies-arrayexpress

Increased CLL Proliferation upon IgM stimulation is Sustained by the Up-regulation of miR-132 and miR-212: a Combined miRNA and Gene Expression Profiling Analysis and Correlation with Disease Progression [gene expression]

Project description:In order to investigate a potential involvement of miRNAs in BCR stimulation, in the present work we first evaluated their expression following IgM cross-linking in CLL cells, as well as in healthy B lymphocytes. Next, to infer putative miRNA targeting networks, we combined miRNA profiling results with gene expression and functional analyses Gene expression profiling analysis by microarray analysis of CLL samples.

2015-02-10 | E-GEOD-49695 | biostudies-arrayexpress

Project description:In order to investigate a potential involvement of miRNAs in BCR stimulation, in the present work we first evaluated their expression following IgM cross-linking in CLL cells, as well as in healthy B lymphocytes. Next, to infer putative miRNA targeting networks, we combined miRNA profiling results with gene expression and functional analyses miRNA expression profiling analysis by microarray analysis of CLL samples and pools of CD19+ cells derived from healthy donors.

2015-02-10 | E-GEOD-49696 | biostudies-arrayexpress

Gene signature of CLL cells cultured with activated T cells or CD40L-expressing cells

Project description:Chronic Lymphocytic Leukemia (CLL) cells multiply in secondary lymphoid tissue but the mechanisms leading to their proliferation are still uncertain. In addition to BCR-triggered signals, other microenvironmental factors might well be involved. In proliferation centres, leukemic B cells are in close contact with CD4+CD40L+Â T cells. Therefore, we here dissected the signals provided by autologous activated T cells (Tact) to CLL cells. Although the gene expression profile induced by Tact was highly similar to that induced by sole CD40 signaling, an obvious difference was that Tact induced proliferation of CLL cells. We determined that stimulation with only CD40L+IL-21 was sufficient to induce robust proliferation in CLL cells. We then defined an IL-21-induced gene signature in CLL, containing components of JAK-STAT and apoptosis pathways, and this signature could be detected in lymph node (LN) samples from patients. Finally, we could detect IL-21 RNA and protein in LN, and IL-21 productionÂ ex vivoÂ by LN CD4+CXCR5+ follicular helper T cells. These results indicate that, in addition to BCR signaling, activated T cells might contribute to CLL cell proliferation via CD40 and IL-21. Targeting these signaling pathways might offer new venues for treatment of CLL.Â CLL cells were cultured under different conditions for 16 hours and then sorted to purity as CD20+ CD5+ cells.

2013-10-07 | E-GEOD-50572 | biostudies-arrayexpress

Gene signature of CLL cells cultured with activated T cells or CD40L-expressing cells

Project description:Chronic Lymphocytic Leukemia (CLL) cells multiply in secondary lymphoid tissue but the mechanisms leading to their proliferation are still uncertain. In addition to BCR-triggered signals, other microenvironmental factors might well be involved. In proliferation centres, leukemic B cells are in close contact with CD4+CD40L+ T cells. Therefore, we here dissected the signals provided by autologous activated T cells (Tact) to CLL cells. Although the gene expression profile induced by Tact was highly similar to that induced by sole CD40 signaling, an obvious difference was that Tact induced proliferation of CLL cells. We determined that stimulation with only CD40L+IL-21 was sufficient to induce robust proliferation in CLL cells. We then defined an IL-21-induced gene signature in CLL, containing components of JAK-STAT and apoptosis pathways, and this signature could be detected in lymph node (LN) samples from patients. Finally, we could detect IL-21 RNA and protein in LN, and IL-21 production ex vivo by LN CD4+CXCR5+ follicular helper T cells. These results indicate that, in addition to BCR signaling, activated T cells might contribute to CLL cell proliferation via CD40 and IL-21. Targeting these signaling pathways might offer new venues for treatment of CLL.

2013-10-07 | GSE50572 | GEO

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

Comparative gene expression analysis upon stimulation of the human BCR or an inducible LMP2A in EBV immortalized lymphoblastoid cell lines

Project description:Survival of all B cells depends on signals from the B-cell receptor (BCR). In BCRnegative B cells the latent membrane protein 2A (LMP2A) of Epstein-Barr virus (EBV) replaces this survival signal and might play a role in the development of EBV-positive Hodgkin lymphomas and posttransplantation lymphoproliferative disease. In these BCR-negative cells LMP2A provides a ‘tonic’ signal similar to BCR’s constitutive expression in the absence of antigen in order to maintain activating signaling pathways common to both receptor molecules. In most latently EBV-infected B cells LMP2A and BCR are co-expressed but it is largely unclear what LMP2A contributes with respect to B-cell activation, proliferation and viral latency in these BCR-positive cells. A common model suggests that LMP2A maintains herpesviral latency by blocking BCR-mediated signals but how LMP2A could serve both antithetical ends in BCRnegative and BCR-positive cells is elusive. Our comparative analysis of BCR and LMP2A now indicates that LMP2A is a true BCR mimic that dominates BCR-operated signaling pathways in EBV-infected, BCR-positive cells to provide activation signals, support stable infections in vivo and allow exit from latency. These findings suggest that LMP2A co-opts the situation in anergic B cells, where continuous BCR signaling results in maintenance of the anergic state accompanied by unresponsiveness to acute BCR stimulation. The microarray experiment was used to compare effects of BCR and LMP2A on gene expression regulation. EBV's LMP2A and the human BCR activate similar cellular target genes; some genes are regulated solely by BCR or LMP2A, no gene is counter regulated A 12 chip study using cDNA from three separate 2525 LMP2A knockout LCL cultures and three separate 3696.10 LMP2A:mCD69 LCL cultures; each culture tested before and after 90 min stimulation of the BCR and LMP2A:mCD69, respectively.

2011-01-01 | E-GEOD-25434 | biostudies-arrayexpress

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