Multi-platform profiling characterizes molecular subgroups and resistance networks in chronic lymphocytic leukemia

Johannes Bloehdorn (), Andrejs Braun, Amaro Taylor-Weiner, Billy Michael Chelliah Jebaraj, Sandra Robrecht, Julia Krzykalla, Heng Pan, Adam Giza, Gulnara Akylzhanova, Karlheinz Holzmann, Annika Scheffold, Harvey E. Johnston, Ru-Fang Yeh, Tetyana Klymenko, Eugen Tausch, Barbara Eichhorst, Lars Bullinger, Kirsten Fischer, Martin Weisser, Tadeusz Robak, Christof Schneider, John Gribben, Lekh N. Dahal, Mathew J. Carter, Olivier Elemento, Dan A. Landau, Donna S. Neuberg, Mark S. Cragg, Axel Benner, Michael Hallek, Catherine J. Wu, Hartmut Döhner, Stephan Stilgenbauer and Daniel Mertens ()
Additional contact information
Johannes Bloehdorn: University of Ulm
Andrejs Braun: Queen Mary University of London
Amaro Taylor-Weiner: Broad Institute of Harvard and MIT
Billy Michael Chelliah Jebaraj: University of Ulm
Sandra Robrecht: University of Cologne
Julia Krzykalla: German Cancer Research Center
Heng Pan: Weill Cornell Medicine
Adam Giza: University of Cologne
Gulnara Akylzhanova: Queen Mary University of London
Karlheinz Holzmann: Ulm University
Annika Scheffold: University of Ulm
Harvey E. Johnston: University of Southampton
Ru-Fang Yeh: Biostatistics, Genentech Inc.
Tetyana Klymenko: Queen Mary University of London
Eugen Tausch: University of Ulm
Barbara Eichhorst: University of Cologne
Lars Bullinger: Charité University Hospital
Kirsten Fischer: University of Cologne
Martin Weisser: Roche Pharma Research and Early Development
Tadeusz Robak: Medical University of Lodz
Christof Schneider: University of Ulm
John Gribben: Queen Mary University of London
Lekh N. Dahal: University of Southampton
Mathew J. Carter: University of Southampton
Olivier Elemento: Weill Cornell Medicine
Dan A. Landau: Weill Cornell Medicine
Donna S. Neuberg: Dana-Farber Cancer Institute
Mark S. Cragg: University of Southampton
Axel Benner: German Cancer Research Center
Michael Hallek: University of Cologne
Catherine J. Wu: Broad Institute of Harvard and MIT
Hartmut Döhner: University of Ulm
Stephan Stilgenbauer: University of Ulm
Daniel Mertens: University of Ulm

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Knowledge of the genomic landscape of chronic lymphocytic leukemia (CLL) grows increasingly detailed, providing challenges in contextualizing the accumulated information. To define the underlying networks, we here perform a multi-platform molecular characterization. We identify major subgroups characterized by genomic instability (GI) or activation of epithelial-mesenchymal-transition (EMT)-like programs, which subdivide into non-inflammatory and inflammatory subtypes. GI CLL exhibit disruption of genome integrity, DNA-damage response and are associated with mutagenesis mediated through activation-induced cytidine deaminase or defective mismatch repair. TP53 wild-type and mutated/deleted cases constitute a transcriptionally uniform entity in GI CLL and show similarly poor progression-free survival at relapse. EMT-like CLL exhibit high genomic stability, reduced benefit from the addition of rituximab and EMT-like differentiation is inhibited by induction of DNA damage. This work extends the perspective on CLL biology and risk categories in TP53 wild-type CLL. Furthermore, molecular targets identified within each subgroup provide opportunities for new treatment approaches.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25403-y

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DOI: 10.1038/s41467-021-25403-y

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