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.


Study overview

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

Chromatin profiling in six immune cell types identifies ibrutinib-induced regulatory changes beyond CLL cells

Single-cell RNA-seq uncovers patient-to-patient heterogeneity in the molecular response to ibrutinib treatment

Ibrutinib treatment induces a quiescent-like state in CLL cells that is shared with other immune cells

Data

This section provides access to raw data and analysis results underlying the presented temporal analysis of ibrutinib-treated CLL.

Name Description and link
Raw and processed ATAC-seq and scRNA-seq data GEO SuperSeries accession: GSE111015
GEO Series on ATAC-seq data: GSE111013
GEO Series on scRNA-seq data: GSE111014
Temporal immunophenotyping of CLL patients during ibrutinib therapy
Immune cell type composition: download here
Expression of surface receptor markers: download here
Temporal chromatin changes in sorted immune cell types of CLL patients during ibrutinib therapy download here
Temporal expression changes in single cells of peripheral blood of CLL patients during ibrutinib therapy download here

Citation

If you use these data in your research, please cite:

André F. Rendeiro1*, Thomas Krausgruber1*, Nikolaus Fortelny1, Fangwen Zhao1, Thomas Penz1, Matthias Farlik1, Linda C. Schuster1, Amelie Kuchler1, Szabolcs Tasnády2, Marienn Réti2, Mátrai Zoltán2, Donat Alpar1†, Csaba Bödör3†, Christian Schmidl1,6†, Christoph Bock1,4,6† (2018).
Chromatin mapping and single-cell immune profiling defines the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia.


* These authors contributed equally to this work
Co-last author / These authors jointly directed this work