Modulation of immune system mediated by ibrutinib in chronic lymphocytic leukemia
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE142292 | GEO | 2020/09/18
REPOSITORIES: GEO
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Project description:In the marrow and lymphatic tissues, chronic lymphocytic leukemia (CLL) cells interact with accessory cells that constitute the leukemia microenvironment. In lymphatic tissues, CLL cells are interspersed with CD68+ nurselike cells (NLC) and T cells. However, the mechanism regulating co-localization of CLL cells and these accessory cells are largely unknown. To dissect the molecular cross-talk between CLL and NLC, we profiled the gene expression of CD19-purified CLL cells before and after co-culture with NLC. NLC co-culture induced high-level expression of B cell maturation antigen (BCMA) and two chemoattractants (CCL3, CCL4) by CLL cells. Supernatants from CLL-NLC co-cultures revealed high CCL3/CCL4 protein levels. B cell receptor triggering also induced a robust induction of CCL3 and CCL4 expression by CLL cells, which was almost completely abrogated by a specific Syc inhibitor, R406. High CCL3 and CCL4 plasma levels in CLL patients suggest that activation of this pathway plays a role in vivo. These studies reveal a novel mechanism of cross-talk between CLL cells and their microenvironment, namely the secretion of two T cell chemokines by CLL-NLC interaction and in response to BCR stimulation. Through these chemokines, CLL cells can recruit accessory cells, and thereby actively create a microenvironment that favors their growth and survival. Experiment Overall Design: The microarray part of this study included samples of CLL cells from 9 different patients, analyzed directly after purification and after 14 days of co-culture with Nurse like cells . Experiment Overall Design: In detail, RNA was isolated from CD19-purified CLL cells from 9 different patientsâ peripheral blood mononuclear cells (PBMC) after Ficoll separation and subsequent purification with CD19 MicroBeads and the MACS® technology according to the manufacturerâs instructions (Miltenyi Biotec, Bergisch Gladbach, Germany). For comparison, the same CLL cell samples were co-cultured for 14 days with NLC (""14d NLC"").""). For co-culture with NLC, PBMC from patients with CLL were suspended in complete RPMI medium (RPMI1640 with 10% FCS, penicillin-streptomycin-glutamine, Gibco-BRL, Grand Island, NY) to a concentration of 1 x 107/ml (total 20 ml) and incubated for 14 days in 75 cm2 tissue culture flasks (Techno Plastic Products AG) as described previously3. Nonadherent lymphoid cells then were removed and the NLC layer was washed two times with phosphate-buffered saline (PBS). The complete removal of lymphocytes was verified by phase-contrast microscopy. The nonadherent cells together with the wash-fractions were then used for RNA preparation. In order to purify the CLL B cells prior to RNA isolation, CLL PBMC were passed through a 30 µm nylon mesh to obtain a single-cell suspension. Then CLL B cells were purified with CD19 MicroBeads. Subsequently RNA was extracted.
2009-01-13 | E-GEOD-13811 | biostudies-arrayexpress
Project description:The study of the roles of macrophages in the microenvironment of cancer cells (tumor-associated macrophages, TAM) has gained deep insight over the recent years. Here, we describe gene expression profile of chronic lymphocytic leukemia (CLL)-associated macrophages, also called nurse-like cells (NLC), derived from in vitro co-cultures system. We define these NLC as M2-oriented, TAM-like specific subset of macrophages, with very few inter-individual variations in gene expression profiles. CLL patients PBMC were isolated and cultured for 15 days in vitro. NLC were then isolated, mRNA were purified and hybridized on Affymetrix U133 plus 2.0 chips. Data were normalized by RMA5
2012-12-11 | E-GEOD-42733 | biostudies-arrayexpress
Project description:The study of the roles of macrophages in the microenvironment of cancer cells (tumor-associated macrophages, TAM) has gained deep insight over the recent years. Here, we describe gene expression profile of chronic lymphocytic leukemia (CLL)-associated macrophages, also called nurse-like cells (NLC), derived from in vitro co-cultures system. We define these NLC as M2-oriented, TAM-like specific subset of macrophages, with very few inter-individual variations in gene expression profiles.
2012-12-11 | GSE42733 | GEO
Project description:In the marrow and lymphatic tissues, chronic lymphocytic leukemia (CLL) cells interact with accessory cells that constitute the leukemia microenvironment. In lymphatic tissues, CLL cells are interspersed with CD68+ nurselike cells (NLC) and T cells. However, the mechanism regulating co-localization of CLL cells and these accessory cells are largely unknown. To dissect the molecular cross-talk between CLL and NLC, we profiled the gene expression of CD19-purified CLL cells before and after co-culture with NLC. NLC co-culture induced high-level expression of B cell maturation antigen (BCMA) and two chemoattractants (CCL3, CCL4) by CLL cells. Supernatants from CLL-NLC co-cultures revealed high CCL3/CCL4 protein levels. B cell receptor triggering also induced a robust induction of CCL3 and CCL4 expression by CLL cells, which was almost completely abrogated by a specific Syc inhibitor, R406. High CCL3 and CCL4 plasma levels in CLL patients suggest that activation of this pathway plays a role in vivo. These studies reveal a novel mechanism of cross-talk between CLL cells and their microenvironment, namely the secretion of two T cell chemokines by CLL-NLC interaction and in response to BCR stimulation. Through these chemokines, CLL cells can recruit accessory cells, and thereby actively create a microenvironment that favors their growth and survival.
2008-12-11 | GSE13811 | GEO
Project description:Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in developed countries. Ibrutinib (PCI-32765), a specific and irreversible inhibitor of Bruton's Tyrosine Kinase (BTK) represents a major step forward in the treatment of CLL. We have undertaken a detailed analysis of the changes happening to the chromatin structure in CLL cells from patients continuously receiving oral doses of ibrutinib. ChIP-seq has been performed for H3K4me3, H3K27ac, H3K27me3 and EZH2 up to 56 days following the beginning of the treatment. We observed that Ibrutinib-dependent lymphocytosis correlates with a global and transient recruitment of EZH2 to active cis-regulatory elements and increased H3K27me3.
2019-06-01 | E-MTAB-6410 | biostudies-arrayexpress
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
Project description:Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in developed countries. Ibrutinib (PCI-32765), a specific and irreversible inhibitor of Bruton's Tyrosine Kinase (BTK) represents a major step forward in the treatment of CLL, but cases of resistance are emerging. We have undertaken a detailed analysis of the changes happening to the chromatin structure in CLL cells from two patients on ibrutinib and showing disease progression. ChIP-seq has been performed for H3K4me3, H3K27ac and H3K27me3. We observed chromatin alterations independent of the disease progression. Raw data is available in EGA under controlled access with accession EGAD00001005220
2020-09-01 | E-MTAB-8220 | biostudies-arrayexpress
Project description:Ibrutinib, an irreversible Bruton Tyrosine Kinase (BTK) inhibitor, has revolutionized Chronic Lymphocytic Leukemia (CLL) treatment, but resistances to ibrutinib have emerged in relation or not to BTK mutations. Evolution patterns of CLL before and after ibrutinib therapy are often focused only on leukemic cells but must be investigated in the context of the CLL microenvironment. Single cell RNA-seq and related technologies allow a deeper characterization of cancer and normal cells. We therefore investigated whether ibrutinib treatment drives molecular changes in CLL. Here, we report the monitoring of a CLL patient under ibrutinib treatment using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-Seq) technology. We report that the short clinical relapse of this patient, driven by BTK mutation, is associated with intra-clonal heterogeneity and transcriptional and phenotypical modifications in both B leukemic and immune cells. These results open new therapeutic strategies for ibrutinib-refractory CLL patients.
2020-12-15 | GSE152469 | GEO
Project description:miRs were discovered to be significantly differentially regulated after ibrutinib therapy Peripheral blood CLL cell samples at pre-treatment, after 2hrs, 24hrs, 8 days, 29 days after threapy were collected and RNA was collected and used for miR nanostring analysis.
2017-01-25 | GSE84801 | GEO
Project description:Chronic lymphocytic leukemia (CLL) is a genetically, epigenetically, and clinically heterogeneous disease. Despite this heterogeneity, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib provides effective treatment for the vast majority of CLL patients. To define the underlining regulatory program, we analyzed high-resolution time courses of ibrutinib treatment in closely monitored patients, combining cellular phenotyping (flow cytometry), single-cell transcriptome profiling (scRNA-seq), and chromatin mapping (ATAC-seq). We identified a consistent regulatory program shared across all patients, which was further validated by an independent CLL cohort. In CLL cells, this program starts with a sharp decrease of NF-κB binding, followed by reduced regulatory activity of lineage-defining transcription factors (including PAX5 and IRF4) and erosion of CLL cell identity, finally leading to the acquisition of a quiescence-like gene signature which was shared across several immune cell types. Nevertheless, we observed patient-to-patient variation in the speed of its execution, which we exploited to predict patient-specific dynamics in the response to ibrutinib based on pre-treatment samples. In aggregate, our study describes the cellular, molecular, and regulatory effects of therapeutic B cell receptor inhibition in CLL at high temporal resolution, and it establishes a broadly applicable method for epigenome/transcriptome-based treatment monitoring. This SuperSeries is composed of the SubSeries listed below.
2019-02-22 | GSE111015 | GEO