Lenaliddomide + IL21 in CLL
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE79660 | GEO | 2017/05/01
SECONDARY ACCESSION(S): PRJNA316615
REPOSITORIES: GEO
Similar Datasets
Project description:The importance of the stromal microenvironment in chronic lymphocytic leukemia (CLL) pathogenesis and drug resistance is well established. Despite recent advances in CLL therapy, identifying novel ways to disrupt interactions between CLL and its microenvironment may identify new combination partners for the drugs currently in use. To understand the role of microenvironmental factors on primary CLL cells, we took advantage of an observation that conditioned media (CM) collected from stroma was protective of CLL cells from spontaneous cell death ex vivo. The cytokine in the CM-dependent cells that most supports CLL survival in short term ex-vivo culture was CCL2. Pre-treatment of CLL cells with anti-CCL2 antibody enhanced venetoclax-mediated killing. Surprisingly, we found a group of CLL samples (9 of 23 cases) that are less likely to undergo cell death in the absence of CM support. Functional studies revealed that CM-independent (CMI) CLL cells are less sensitive to apoptosis than conventional stroma-dependent CLL. Additionally, a majority of the CMI CLL samples (80%) harbored unmutated IGHV. Bulk-RNA Seq analysis revealed upregulation of the focal adhesion and Ras signaling pathways in this group, along with expression of FLT3 and CD135 expression. Treatment with FLT3 inhibitors caused a significant reduction in cell viability among CMI samples. In summary, we were able to discriminate and target two biologically distinct subgroups of CLL based on CM dependence with distinct microenvironmental vulnerabilities.
2023-09-01 | GSE237907 | GEO
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
Project description:Inactivating mutations in the NF-kB inhibitor NFKBIE are frequent in chronic lymphocytic leukemia (CLL) and have been associated with accelerated disease progression and inferior responses to chemotherapy. To further understand the role of NFKBIE mutations in CLL, we disrupted by CRISPR/Cas9 editing the NFKBIE gene in CLL cells derived from the Eμ-TCL1 transgenic mouse model and investigated how this will affect CLL growth and response to B cell receptor inhibitor treatment. In vitro and adoptive transfer experiments showed that NFKBIE-mutated cells have a growth advantage over NFKBIE-wild type cells when exposed to microenvironmental signals that activate the canonical NF-kB pathway and can induce alterations within the tumor microenvironment that may allow for escape from immune surveillance, including the expansion of CD8+ T cells with an exhausted phenotype and increased expression of PD-L1 on the malignant B cells. Consistent with these findings, significantly greater expression of the exhaustion markers PD1 and TIGIT was observed on T cells from CLL patients with NFKBIE-mutated compared to NFKBIE-wild type leukemia. In addition, in vitro and in vivo experiments showed that NFKBIE-mutated murine CLL cells are selectively resistant to BTK inhibitor treatment while remaining sensitive to treatment with a PI3K or SYK inhibitor. Reduced sensitivity to BTK inhibitor treatment was also observed in a series of 229 ibrutinib-treated CLL patients showing inferior outcomes for the NFKBIE-mutated cases. These findings provide evidence that NFKBIE-mutated CLL cells reshape and are selected by the tumor microenvironment and may account for suboptimal ibrutinib responses.
2024-01-29 | GSE231799 | GEO
Project description:We studied whether Vγ9Vδ2-T cells can exploited as autologous effector lymphocytes in chronic lymphocytic leukemia (CLL). Healthy controls (HC) Vγ9Vδ2-T cells were activated by and had potent cytolytic activity against CLL cells, however CLL-derived Vγ9Vδ2-T cells proved dysfunctional with respect to effector cytokine production and cytotxicity. Dysfunction of Vγ9Vδ2-T cells was reversible upon activation with autologous monocyte-derived dendritic cells (mODCs). RNA sequencing confirmed that Vγ9Vδ2-T cells from CLL patients have a transcriptional profile that is distinct from HC Vγ9Vδ2-T cells prior to ex vivo expansion, although the profile after ex vivo expansion is similar between CLL and HC Vγ9Vδ2-T cells. Gene expression profiling implicated alterations in both synapse formation and exhaustion as conceivable contributors to compromised Vγ9Vδ2-T cell function in CLL patients. Taken together, CLL-mediated dysfunction of autologous Vγ9Vδ2-T cells is fully reversible, resulting in potent cytotoxicity towards CLL cells.
| EGAS00001003193 | EGA
Project description:Chronic lymphocytic leukemia (CLL) is a malignant lymphoproliferative disorder characterized by the accumulation of small mature B cells in blood and secondary lymphoid tissues. Novel drugs, such as the Bruton tyrosine kinase (BTK) inhibitor ibrutinib, have greatly improved survival of CLL patients, nevertheless acquired drug resistance represents a major challenge the molecular mechanisms of which have not been fully elucidated yet. To overcome this limitation, we generated a mouse model of ibrutinib resistance by treating mice upon adoptive transfer of Eµ-TCL1 leukemia (TCL1-CLL) continuously with ibrutinib. After an initial response to the treatment, relapse under therapy occurs with an aggressive outgrowth of malignant cells, resembling observations in patients. To unravel relapse mechanism, we performed transcriptome and proteome analyses of sorted TCL1-CLL cells both during treatment and after relapse. Comparative analysis of these omics layers suggested alterations in the proteasome activity as a driver of ibrutinib resistance. Accordingly, we showed that preclinical treatment with the irreversible proteasome inhibitor (PI) carfilzomib administered upon ibrutinib resistance prolonged survival of mice, thus acting as salvage therapy. Longitudinal proteomic analysis of CLL patients with ibrutinib resistance identified deregulation in protein post-translational modifications. In addition, CLL cells from ibrutinib-resistant patients effectively responded to several PIs in co-culture assays. Altogether, our results from orthogonal omics approaches identified proteasome inhibition as potentially attractive salvage treatment option for CLL patients resistant or refractory to ibrutinib.
2024-12-10 | PXD053512 | Pride
Project description:In this study, using ChIP sequencing, we identified EZH2 target genes in two prognostic subgroups of chronic lymphocytic leukemia with distinct outcome, i.e. IGHV-unmutated/subset #1 and IGHV-mutated/subset #4. Our data identified many oncogenic pathways enriched equally by EZH2 target genes in both prognostic subgroups. Importantly, we identified PI3K pathway as differentially enriched pathway by EZH2 between the two prognostic sub groups. Validation of EZH2 target genes for EZH2 occupancy on selected PI3K pathway target genes were performed using independent CLL patient samples and CLL cell lines using siRNA mediated down regulation and ChIP assays. In conclusion, for the first time we characterized EZH2 target genes in CLL to understand the role of EZH2 in regulating the oncogenic pathways for improved therapeutic intervention and designing better drugs for targeting EZH2 in CLL.
2019-06-24 | GSE115772 | GEO
Project description:We used microarrays to analyze gene expression following treatment of leukemic B cells with the Hsp90 inhibitor 17-DMAG. Gene expression profiling reveals the role of SOCS3 in cytokine signaling in CLL Primary cells from CLL patients were isolated and treated in vitro with 17-DMAG. Cells were collected for viability, gene expression analysis and cell signaling and migration assays.
2016-07-01 | E-GEOD-76546 | biostudies-arrayexpress
Project description:Purpose: It has been proposed that vitamin D may play a role in prevention and treatment of cancer while epidemiological studies have linked vitamin D insufficiency to adverse disease outcome in chronic lymphocytic leukemia (CLL). However, the underlying mechanisms have not yet been revealed. In this study, we sought to identify key signaling pathways and molecules that are altered after calcitriol, the biologically active form of vitamin D, supplementation of CLL cells in vitro. Methods: An RNA-Sequencing analysis was performed in primary CLL cells that were treated in vitro with calcitriol. Total RNA was extracted from calcitriol-treated and non-treated CLL cells, while mRNA selection was performed using NEBNext Poly(A) mRNA Magnetic Isolation Module. Library preparation for RNA-Sequencing (RNA-Seq) analysis was conducted with the NEBNext Ultra II Directional RNA Library Prep Kit. The libraries were paired-end sequenced on the NextSeq 500 Illumina platform. Differential expression analysis was performed using DESeq2; genes with log2FC>|1| and P≤0.05 were considered as differentially expressed. Results: Differential expression analysis revealed 85 differentially expressed genes (DEGs) (log2FC≥|1| and p≤0.05), of which 28 (32.9%) were overexpressed in calcitriol-treated cells versus unstimulated CLL cells, thus, contrasting the remaining 57 (67.1%) which showed the opposite pattern. Supervised hierarchical clustering analysis, based on the differentially expressed genes, was performed and revealed distinct gene expression patterns between calcitriol-treated and control CLL cells. Moreover, pathway enrichment analysis revealed that calcitriol-regulated genes are implicated in signaling pathways known to be deregulated in CLL biology. Conclusions: Transcriptome analysis highlighted the possible impact of calcitriol on the regulation of immune signaling pathways relevant to CLL pathophysiology.
2021-01-01 | GSE162427 | GEO
Project description:To elucidate effects of tumor host interactions in vivo in CLL, purified tumor cells were obtained concurrently from blood, bone marrow and/or lymph node and analyzed by gene expression profiling. Keywords: RNA Comparision of gene expression profiling in matched pairs of peripheral blood (PB) vs. bone marrow (BM) or lymph nodes (LN) derived CLL cells
2010-10-01 | E-GEOD-21029 | biostudies-arrayexpress
Project description:The B-cell receptor (BCR) plays an important role in pathogenesis and progression of chronic lymphocytic leukemia (CLL). We investigated the BCR triggering-dependent microRNA modulation by stimulating CLL cells with immobilized anti-IgM. miRome of immobilized anti-IgM stimulated CLL cells (n=16) identified a substantial upregulation of miR-132 in both unmutated (UM) and mutated (M) IGHV subgroups. A parallel gene expression profile and an in-silico analysis to identify miR-132 target genes¸ allowed us to focus on SIRT1, that encodes for a histone deacetylase targeting several proteins including TP53. We defined a reduction of SIRT1 protein levels upon immobilized anti-IgM stimulation (P=0.001), and a concomitant increase in TP53 acetylation (P=0.0072). The TP53 target gene CDKN1A was consistently up-regulated in immobilized anti-IgM stimulated CLL cells. Of note, the miR-132 constitutive expression levels in CLL cases (n=134) were of similar magnitude of those obtained in in vitro immobilized anti-IgM stimulated CLL cells. Additionally, high miR-132 expression levels retained a favorable prognostic impact in M (P=0.005), but not in UM CLL patients (P=0.968). The described miR-132/SIRT1/TP53 axis, sequentially characterized by BCR triggering, miR-132 up-regulation, SIRT1 down-regulation and TP53 acetylation, should be considered in the light of emerging drugs targeting the BCR pathway in CLL. investigated the BCR triggering-dependent gene expression modulation by stimulating CLL cells with immobilized anti-IgM.
2014-01-01 | E-GEOD-52775 | biostudies-arrayexpress