Multi-platform profiling characterizes molecular subgroups and resistance networks in chronic lymphocytic leukemia
| Autor: | Bloehdorn, Johannes, Braun, Andrejs, Taylor-Weiner, Amaro, Jebaraj, Billy Michael Chelliah, Robrecht, Sandra, Krzykalla, Julia, Pan, Heng, Giza, Adam, Akylzhanova, Gulnara, Holzmann, Karlheinz, Scheffold, Annika, Johnston, Harvey E., Yeh, Ru-Fang, Klymenko, Tetyana, Tausch, Eugen, Eichhorst, Barbara, Bullinger, Lars, Fischer, Kirsten, Weisser, Martin, Robak, Tadeusz, Schneider, Christof, Gribben, John G., Dahal, Lekh N., Carter, Mathew J., Elemento, Olivier, Landau, Dan A., Neuberg, Donna S., Cragg, Mark S., Benner, Axel, Hallek, Michael, Wu, Catherine J. |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: | |
| Popis: | 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. publishedVersion |
| Databáze: | OpenAIRE |
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