%0 Journal Article
%A Bloehdorn, Johannes
%A Braun, Andrejs
%A Taylor-Weiner, Amaro
%A Jebaraj, Billy Michael Chelliah
%A Robrecht, Sandra
%A Krzykalla, Julia
%A Pan, Heng
%A Giza, Adam
%A Akylzhanova, Gulnara
%A Holzmann, Karlheinz
%A Scheffold, Annika
%A Johnston, Harvey E
%A Yeh, Ru-Fang
%A Klymenko, Tetyana
%A Tausch, Eugen
%A Eichhorst, Barbara
%A Bullinger, Lars
%A Fischer, Kirsten
%A Weisser, Martin
%A Robak, Tadeusz
%A Schneider, Christof
%A Gribben, John
%A Dahal, Lekh N
%A Carter, Mathew J
%A Elemento, Olivier
%A Landau, Dan A
%A Neuberg, Donna S
%A Cragg, Mark S
%A Benner, Axel
%A Hallek, Michael
%A Wu, Catherine J
%A Döhner, Hartmut
%A Stilgenbauer, Stephan
%A Mertens, Daniel
%T Multi-platform profiling characterizes molecular subgroups and resistance networks in chronic lymphocytic leukemia.
%J Nature Communications
%V 12
%N 1
%@ 2041-1723
%C [London]
%I Nature Publishing Group UK
%M DKFZ-2021-02076
%P 5395
%D 2021
%Z #LA:B061#
%X 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.
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:34518531
%2 pmc:PMC8438057
%R 10.1038/s41467-021-25403-y
%U https://inrepo02.dkfz.de/record/172528