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Chromatin mapping and single-cell immune profiling defines the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia [scRNA-seq]

ABSTRACT: Chromatin mapping and single-cell immune profiling defines the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia [scRNA-seq]

PROVIDER: PRJNA435591 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6762980_1.fastq.gz	Fastqsanger.gz
	SRR6762980_2.fastq.gz	Fastqsanger.gz
	SRR6762981_1.fastq.gz	Fastqsanger.gz
	SRR6762981_2.fastq.gz	Fastqsanger.gz
	SRR6762982_1.fastq.gz	Fastqsanger.gz

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Chromatin mapping and single-cell immune profiling defines the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia

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

Chromatin mapping and single-cell immune profiling defines the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia [scRNA-seq]

2019-02-22 | GSE111014 | GEO

Chromatin mapping and single-cell immune profiling defines the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia [ATAC-seq]

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Chromatin mapping and single-cell immune profiling defines the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia

Project description:Chromatin mapping and single-cell immune profiling defines the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia

| PRJNA435588 | ENA

Chromatin mapping and single-cell immune profiling defines the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia [ATAC-seq]

Project description:Chromatin mapping and single-cell immune profiling defines the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia [ATAC-seq]

| PRJNA435593 | ENA

Ibrutinib induces a global chromatin reorganisation in chronic lymphocytic leukaemia

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

Modulation of immune system mediated by ibrutinib in chronic lymphocytic leukemia

Project description:Our project is based on the hypothesis that ibrutinib could interfere with chronic lymphocytic leukemia (CLL) microenvironment, modulating the immune response. The aim of the project is to understand if and how ibrutinib modifies the tumor microenvironment accessory cells in CLL, specifically nurse like cells (NLC).

2020-09-18 | GSE142292 | GEO

Chromatin structure analysis for two patients on Ibrutinib and showing disease progression in chronic lymphocytic leukaemia

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

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

Modulation of immune system mediated by ibrutinib in chronic lymphocytic leukemia

Project description:Modulation of immune system mediated by ibrutinib in chronic lymphocytic leukemia

| PRJNA596472 | ENA