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

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.; Mertens, D.

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:	Bloehdorn, J. ORCID: https://orcid.org/0000-0003-1433-9702, Braun, A. ORCID: https://orcid.org/0000-0003-0925-5598, 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. ORCID: https://orcid.org/0000-0002-5890-5510, Fischer, K., Weisser, M., Robak, T. ORCID: https://orcid.org/0000-0002-3411-6357, Schneider, C., Gribben, J. ORCID: https://orcid.org/0000-0002-8505-7430, Dahal, L.N. ORCID: https://orcid.org/0000-0001-8390-6593, Carter, M.J., Elemento, O. ORCID: https://orcid.org/0000-0002-8061-9617, Landau, D.A. ORCID: https://orcid.org/0000-0003-2346-9541, Neuberg, D.S. ORCID: https://orcid.org/0000-0003-2566-3145, Cragg, M.S., Benner, A. ORCID: https://orcid.org/0000-0002-7238-6956, Hallek, M., Wu, C.J. ORCID: https://orcid.org/0000-0002-3348-5054, 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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