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

• DOI: 10.1038/s41467-021-25403-y
• Publication Date: 2021-09-13T10:04:04Z
• Authors: Johannes Bloehdorn; Andrejs Braun; Amaro Taylor-Weiner; Billy Michael Che...; 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; Daniel Mertens
• Keywords: Chromosome Aberrations; Cancer Research; 0303 health sciences; Epithelial-Mesenchymal Transition; DNA Repair; Gene Expression Regulation, Leukemic; Science; Gene Expression Profiling; Q; Telomere-Binding Proteins; 610; Ataxia Telangiectasia Mutated Proteins; Leukemia, Lymphocytic, Chronic, B-Cell; Polymorphism, Single Nucleotide; Article; Genomic Instability; Shelterin Complex; 3. Good health; 03 medical and health sciences; Mutation; Humans; Gene Regulatory Networks; Tumor Suppressor Protein p53; DNA Damage

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