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

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

PROVIDER: PRJNA435593 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6762790.fastq.gz	Fastqsanger.gz
	SRR6762800.fastq.gz	Fastqsanger.gz
	SRR6762810.fastq.gz	Fastqsanger.gz
	SRR6762820.fastq.gz	Fastqsanger.gz
	SRR6762830.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.

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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]

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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

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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]

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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.

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