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

Bloehdorn, Johannes, Braun, Andrejs, Taylor-Weiner, Amaro, Jebaraj, Billy Michael Chelliah, Robrecht, Sandra, Krzykalla, Julia, Pan, Heng, Giza, Adam, Akylzhanova, Gulnara, Holzmann, Karlheinz
et al (show 24 more authors) (2021) Multi-platform profiling characterizes molecular subgroups and resistance networks in chronic lymphocytic leukemia. NATURE COMMUNICATIONS, 12 (1). 5395-.

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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.

Item Type: Article
Uncontrolled Keywords: Humans, DNA Damage, Chromosome Aberrations, Genomic Instability, Telomere-Binding Proteins, Gene Expression Profiling, DNA Repair, Gene Expression Regulation, Leukemic, Mutation, Polymorphism, Single Nucleotide, Tumor Suppressor Protein p53, Gene Regulatory Networks, Leukemia, Lymphocytic, Chronic, B-Cell, Epithelial-Mesenchymal Transition, Ataxia Telangiectasia Mutated Proteins, Shelterin Complex
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 27 Jan 2022 09:14
Last Modified: 18 Jan 2023 21:14
DOI: 10.1038/s41467-021-25403-y
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