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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., Braun, A., Taylor-Weiner, A., Jebaraj, B.M.C., Robrecht, S., Krzykalla, J., Pan, H., Giza, A., Akylzhanova, G., Holzmann, K., Scheffold, A., Johnston, H.E., Yeh, R.F., Klymenko, T., Tausch, E., Eichhorst, B., Bullinger, L., Fischer, K., Weisser, M., Robak, T., Schneider, C., Gribben, J., Dahal, L.N., Carter, M.J., Elemento, O., Landau, D.A., Neuberg, D.S., Cragg, M.S., Benner, A., Hallek, M., Wu, C.J., Döhner, H., 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 |
| ISSN: | 2041-1723 |
| Publisher: | Nature Publishing Group |
| Volume: | 12 |
| Number: | 1 |
| 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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