Combined chemosensitivity and chromatin profiling
prioritizes drug combinations in CLL
Supplementary Website
Abstract
The Bruton tyrosine kinase (BTK) inhibitor ibrutinib has substantially improved therapeutic options for chronic lymphocytic leukemia (CLL). Although ibrutinib is not curative, it has a profound effect on CLL cells and may create new pharmacologically exploitable vulnerabilities. To identify such vulnerabilities, we developed a systematic approach that combines epigenome profiling (charting the gene-regulatory basis of cell state) with single-cell chemosensitivity profiling (quantifying cell-type-specific drug response) and bioinformatic data integration. By applying our method to a cohort of matched patient samples collected before and during ibrutinib therapy, we identified characteristic ibrutinib-induced changes that provide a starting point for the rational design of ibrutinib combination therapies. Specifically, we observed and validated preferential sensitivity to proteasome, PLK1, and mTOR inhibitors during ibrutinib treatment. More generally, our study establishes a broadly applicable method for investigating treatment-specific vulnerabilities by integrating the complementary perspectives of epigenetic cell states and phenotypic drug responses in primary patient samples.
Study overview
Integrative analysis of epigenetic cell state and cell-selective chemosensitivity in ibrutinib-treated CLL patients
Biobanked peripheral blood mononuclear cells (PBMCs) from chronic lymphocytic leukemia (CLL) patients isolated before and during ibrutinib treatment were subjected to chromatin accessibility mapping by ATAC-seq and to chemosensitivity profiling using pharmacoscopy, a single-cell automated imaging method for quantifying cell-selective drug response. To connect ibrutinib-induced changes in cell state to induced drug vulnerabilities, we mapped the ATAC-seq and pharmacoscopy data into the shared space of molecular pathways, which provided a joint basis for integrative analysis and prioritization of ibrutinib-based drug combinations for the treatment of CLL and potentially other hematopoietic malignancies.
Genome browser tracks
We performed chromatin accessibility mapping by ATAC-seq on 36 matched primary CLL samples collected before and during ibrutinib treatment.
The following genome browser tracks provide genome-wide maps of ibrutinib's effect on chromatin accessibility and epigenetic cell states:
- Click here to add the track hub to UCSC Genome Browser.
- Click here to add the tracks to a local IGV Genome Browser session (please launch IGV first, e.g. via this URL).
Data
This section provides access to analysis results and data tables underlying the presented analysis of chromatin accessibility and chemosensitivity in ibrutinib-treated CLL.
| Name | Description and link |
|---|---|
| Raw and processed ATAC-seq data | GEO accession: GSE100672 |
| Chromatin regions changing with ibrutinib treatment | Output of differential analysis with DESeq2 CSV file: download here |
| Location overlap analysis (LOLA) of significantly changing chromatin regions with ibrutinib treatment | Output of LOLA analysis for down-regulated regions CSV file: download here Output of LOLA analysis for up-regulated regions CSV file: download here |
| Pharmacoscopy data: CLL-specific sensitivity score | Drug sensitivity score specific to CLL cells versus all other PBMC cell types CSV file: download here |
| Chromatin accessibility data in pathway space: scores per sample | CSV file: download here |
| Data for in-vitro co-culture combinatorial drug sensitivity | CSV file: download here |
Software
To foster reproducibility and facilitate reuse, the source code underlying the analysis is contained in a Git repository at Github and as an archival copy of the git repository.
Citation
If you use these data in your research, please cite:
Christian Schmidl*, Gregory I Vladimer*, André F Rendeiro*, Susanne Schnabl*, Tea Pemovska, Thomas Krausgruber, Mohammad Araghi, Nikolaus Krall, Berend Snijder, Rainer Hubmann, Anna Ringler, Dita Demirtas, Oscar Lopez de la Fuente, Martin Hilgarth, Cathrin Skrabs, Edit Porpaczy, Michaela Gruber, Gregor Hörmann, Stefan Kubicek, Philipp B Staber, Medhat Shehata†, Giulio Superti-Furga†, Ulrich Jäger†, Christoph Bock† (2019). Combined chemosensitivity and chromatin profiling prioritizes drug combinations in CLL. Nature Chemical Biology DOI: 10.1038/s41589-018-0205-2.
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