RT Journal Article
SR Electronic
T1 Chromatin mapping and single-cell immune profiling define the temporal dynamics of ibrutinib drug response in chronic lymphocytic leukemia
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 597005
DO 10.1101/597005
A1 Rendeiro, André F.
A1 Krausgruber, Thomas
A1 Fortelny, Nikolaus
A1 Zhao, Fangwen
A1 Penz, Thomas
A1 Farlik, Matthias
A1 Schuster, Linda C.
A1 Nemc, Amelie
A1 Tasnády, Szabolcs
A1 Réti, Marienn
A1 Mátrai, Zoltán
A1 Alpar, Donat
A1 Bödör, Csaba
A1 Schmidl, Christian
A1 Bock, Christoph
YR 2019
UL http://biorxiv.org/content/early/2019/04/03/597005.abstract
AB 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.