Bloehdorn, Johannes ORCID: 0000-0003-1433-9702, Braun, Andrejs ORCID: 0000-0003-0925-5598, 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 ORCID: 0000-0002-5890-5510, Fischer, Kirsten, Weisser, Martin, Robak, Tadeusz ORCID: 0000-0002-3411-6357, Schneider, Christof, Gribben, John, Dahal, Lekh N., Carter, Mathew J., Elemento, Olivier, Landau, Dan A., Neuberg, Donna S., Cragg, Mark S., Benner, Axel, Hallek, Michael, Wu, Catherine J., Doehner, Hartmut, Stilgenbauer, Stephan and Mertens, Daniel (2021). Multi-platform profiling characterizes molecular subgroups and resistance networks in chronic lymphocytic leukemia. Nat. Commun., 12 (1). BERLIN: NATURE PORTFOLIO. ISSN 2041-1723

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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. Chronic lymphocytic leukemia has been studied using multiple levels of omics data. Here, the authors use exome sequencing, SNP, protein and gene expression data to identify distinct biologic tumor subtypes with heterogeneous prognostic impact after chemo- or immunochemotherapy.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Bloehdorn, JohannesUNSPECIFIEDorcid.org/0000-0003-1433-9702UNSPECIFIED
Braun, AndrejsUNSPECIFIEDorcid.org/0000-0003-0925-5598UNSPECIFIED
Taylor-Weiner, AmaroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jebaraj, Billy Michael ChelliahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Robrecht, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krzykalla, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pan, HengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giza, AdamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Akylzhanova, GulnaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holzmann, KarlheinzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scheffold, AnnikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Johnston, Harvey E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yeh, Ru-FangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klymenko, TetyanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tausch, EugenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eichhorst, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bullinger, LarsUNSPECIFIEDorcid.org/0000-0002-5890-5510UNSPECIFIED
Fischer, KirstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weisser, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Robak, TadeuszUNSPECIFIEDorcid.org/0000-0002-3411-6357UNSPECIFIED
Schneider, ChristofUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gribben, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dahal, Lekh N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carter, Mathew J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Elemento, OlivierUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Landau, Dan A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neuberg, Donna S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cragg, Mark S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benner, AxelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wu, Catherine J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Doehner, HartmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stilgenbauer, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mertens, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-605194
DOI: 10.1038/s41467-021-25403-y
Journal or Publication Title: Nat. Commun.
Volume: 12
Number: 1
Date: 2021
Publisher: NATURE PORTFOLIO
Place of Publication: BERLIN
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
EPITHELIAL-MESENCHYMAL TRANSITION; DNA METHYLATION; CHROMOSOMAL INSTABILITY; GENE-EXPRESSION; FEEDBACK LOOP; P53 ACTIVITY; MUTATIONS; CANCER; GENOME; EVOLUTIONMultiple languages
Multidisciplinary SciencesMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60519

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