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

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Item Type:Article
Title:Multi-platform profiling characterizes molecular subgroups and resistance networks in chronic lymphocytic leukemia
Creators Name:Bloehdorn, J. and Braun, A. and Taylor-Weiner, A. and Jebaraj, B.M.C. and Robrecht, S. and Krzykalla, J. and Pan, H. and Giza, A. and Akylzhanova, G. and Holzmann, K. and Scheffold, A. and Johnston, H.E. and Yeh, R.F. and Klymenko, T. and Tausch, E. and Eichhorst, B. and Bullinger, L. and Fischer, K. and Weisser, M. and Robak, T. and Schneider, C. and Gribben, J. and Dahal, L.N. and Carter, M.J. and Elemento, O. and Landau, D.A. and Neuberg, D.S. and Cragg, M.S. and Benner, A. and Hallek, M. and Wu, C.J. and Döhner, H. and Stilgenbauer, S. and Mertens, D.
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.
Keywords:Ataxia Telangiectasia Mutated Proteins, B-Cell Chronic Lymphocytic Leukemia, Chromosome Aberrations, DNA Damage, DNA Repair, Epithelial-Mesenchymal Transition, Gene Expression Profiling, Gene Regulatory Networks, Genomic Instability, Leukemic Gene Expression Regulation, Mutation, Single Nucleotide Polymorphism, Telomere-Binding Proteins, Tumor Suppressor Protein p53
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:5395
Date:13 September 2021
Official Publication:https://doi.org/10.1038/s41467-021-25403-y
PubMed:View item in PubMed

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