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Nat Commun. 2020 Jan 29;11(1):577. doi: 10.1038/s41467-019-14081-6.

Chromatin mapping and single-cell immune profiling define the temporal dynamics of ibrutinib response in CLL.

Author information

1
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
2
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
3
Department of Haematology and Stem Cell Transplantation, Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary.
4
MTA-SE Lendület Molecular Oncohematology Research Group, 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
5
Regensburg Center for Interventional Immunology (RCI), Regensburg, Germany.
6
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. cbock@cemm.oeaw.ac.at.
7
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria. cbock@cemm.oeaw.ac.at.
8
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria. cbock@cemm.oeaw.ac.at.

Abstract

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib provides effective treatment for patients with chronic lymphocytic leukemia (CLL), despite extensive heterogeneity in this disease. To define the underlining regulatory dynamics, we analyze high-resolution time courses of ibrutinib treatment in patients with CLL, combining immune-phenotyping, single-cell transcriptome profiling, and chromatin mapping. We identify a consistent regulatory program starting with a sharp decrease of NF-κB binding in CLL cells, which is followed by reduced activity of lineage-defining transcription factors, erosion of CLL cell identity, and acquisition of a quiescence-like gene signature. We observe patient-to-patient variation in the speed of execution of this program, which we exploit to predict patient-specific dynamics in the response to ibrutinib based on the pre-treatment patient samples. In aggregate, our study describes time-dependent cellular, molecular, and regulatory effects for therapeutic inhibition of B cell receptor signaling in CLL, and it establishes a broadly applicable method for epigenome/transcriptome-based treatment monitoring.

PMID:
31996669
PMCID:
PMC6989523
DOI:
10.1038/s41467-019-14081-6
[Indexed for MEDLINE]
Free PMC Article

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