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

André F. Rendeiro, Thomas Krausgruber, Nikolaus Fortelny, Fangwen Zhao, Thomas Penz, Matthias Farlik, Linda C. Schuster, Amelie Nemc, Szabolcs Tasnády, Marienn Réti, Zoltán Mátrai, Donát Alpár, Csaba Bödör, Christian Schmidl and Christoph Bock ()
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André F. Rendeiro: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Thomas Krausgruber: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Nikolaus Fortelny: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Fangwen Zhao: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Thomas Penz: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Matthias Farlik: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Linda C. Schuster: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Amelie Nemc: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Szabolcs Tasnády: National Institute of Hematology and Infectious Diseases
Marienn Réti: National Institute of Hematology and Infectious Diseases
Zoltán Mátrai: National Institute of Hematology and Infectious Diseases
Donát Alpár: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Csaba Bödör: Semmelweis University
Christian Schmidl: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Christoph Bock: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14081-6

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