Multi-platform profiling characterizes molecular subgroups and resistance networks in chronic lymphocytic leukemia
Multi-platform profiling characterizes molecular subgroups and resistance networks in chronic lymphocytic leukemia
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.
Cragg, Mark
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Bloehdorn, Johannes
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Braun, Andrejs
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Taylor-Weiner, Amaro
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Chelliah Jebaraj, Billy Michael
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Robrecht, Sandra
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Krzykalla, Julia
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Pan, Heng
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Giza, Adam
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Akylzhanova, Gulnara
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Holzmann, Karlheinz
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Scheffold, Annika
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Johnston, Harvey E.
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Yeh, Ru-Fang
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Klymenko, Tetyana
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Eichorst, Barbara
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Bullinger, Lars
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Fischer, Kirsten
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Weisser, Martin Weisser
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Robak, Tadeusz
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Schneider, Christof
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Gribben, John
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Dahal, Lekh N
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Carter, Matthew J.
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Elemento, Oliver
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Landau, Dan A.
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Neuberg, Donna S.
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Cragg, Mark S.
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Benner, Axel
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Hallek, Michael
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Wu, Catherine J
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Dohner, Hartmut
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Stilgenbauer, Stephan
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Mertens, Daniel
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13 September 2021
Cragg, Mark
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Bloehdorn, Johannes
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Braun, Andrejs
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Taylor-Weiner, Amaro
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Chelliah Jebaraj, Billy Michael
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Robrecht, Sandra
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Krzykalla, Julia
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Pan, Heng
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Giza, Adam
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Akylzhanova, Gulnara
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Holzmann, Karlheinz
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Scheffold, Annika
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Johnston, Harvey E.
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Yeh, Ru-Fang
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Klymenko, Tetyana
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Eichorst, Barbara
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Bullinger, Lars
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Fischer, Kirsten
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Weisser, Martin Weisser
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Robak, Tadeusz
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Schneider, Christof
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Gribben, John
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Dahal, Lekh N
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Carter, Matthew J.
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Elemento, Oliver
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Landau, Dan A.
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Neuberg, Donna S.
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Cragg, Mark S.
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Benner, Axel
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Hallek, Michael
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Wu, Catherine J
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Dohner, Hartmut
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Stilgenbauer, Stephan
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Mertens, Daniel
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Cragg, Mark, Bloehdorn, Johannes, Braun, Andrejs, Taylor-Weiner, Amaro, Chelliah Jebaraj, Billy Michael, Robrecht, Sandra, Krzykalla, Julia, Pan, Heng, Giza, Adam, Akylzhanova, Gulnara, Holzmann, Karlheinz, Scheffold, Annika, Johnston, Harvey E., Yeh, Ru-Fang, Klymenko, Tetyana, Eichorst, Barbara, Bullinger, Lars, Fischer, Kirsten, Weisser, Martin Weisser, Robak, Tadeusz, Schneider, Christof, Gribben, John, Dahal, Lekh N, Carter, Matthew J., Elemento, Oliver, Landau, Dan A., Neuberg, Donna S., Cragg, Mark S., Benner, Axel, Hallek, Michael, Wu, Catherine J, Dohner, Hartmut, Stilgenbauer, Stephan and Mertens, Daniel
(2021)
Multi-platform profiling characterizes molecular subgroups and resistance networks in chronic lymphocytic leukemia.
Nature Communications, 12 (1), [5395].
(doi:10.1038/s41467-021-25403-y).
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.
Text
Deciphering pathogenic networks in CLL - Nat.Com. 04_2021acc
- Accepted Manuscript
More information
Accepted/In Press date: 3 August 2021
Published date: 13 September 2021
Additional Information:
Funding Information:
S.S. received advisory board honoraria, research support, travel support, speaker fees from AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis. O.E. is supported by Janssen, Johnson and Johnson, Volastra Therapeutics, AstraZeneca, and Eli Lilly research grants. He is a scientific advisor and equity holder in Freenome, Owkin, Volastra Therapeutics and One Three Biotech and paid scientific advisor to Champion Oncology. M.S.C. is a retained consultant for BioInvent International and has performed educational and advisory roles for Roche, Boehringer Ingelheim, Baxalta, Merck KGaA, and GLG. He has received research funding from Bioinvent, Roche, Gilead, iTeos, UCB, and GSK. He is co-inventor of patent WO2012022985A1 protecting antibodies directed to hFcgRIIB in combination with CD20 specific antibodies. L.B.: Advisory Committees Abbvie, Amgen, Astellas, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Hexal, Janssen, Jazz Pharmaceuticals, Menarini, Novartis, Pfizer, Sanofi, Seattle Genetics. R-F.Y. and M.W. are employed by Genentech and Roche, respectively. J.B. received travel support from Janssen and research support from Roche. The remaining authors declare no competing interests.
Funding Information:
The authors thank all patients and their physicians for trial participation and donation of samples; the DCLLSG; Sabrina Schrell and Christina Galler for their excellent technical assistance. This work was supported by research grants from the Else Kröner-Fresenius-Stiftung (2010_Kolleg24, 2012_A146), BMBF (PRECISE), Cancer Research UK (A24721 and A18087), Kay Kendall Leukemia Fund (KKL1101), and Blood Cancer UK (19001), European Commission/BMBF (“FIRE CLL”, 01KT160), SFB 1074 (Projects B1, B2), DJCLS R 11/01.
Publisher Copyright:
© 2021, The Author(s).
Identifiers
Local EPrints ID: 451904
URI: http://eprints.soton.ac.uk/id/eprint/451904
ISSN: 2041-1723
PURE UUID: 1387cdff-71f8-468b-aefb-fd7636ad4504
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Date deposited: 03 Nov 2021 17:30
Last modified: 17 Mar 2024 02:46
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Contributors
Author:
Johannes Bloehdorn
Author:
Andrejs Braun
Author:
Amaro Taylor-Weiner
Author:
Billy Michael Chelliah Jebaraj
Author:
Sandra Robrecht
Author:
Julia Krzykalla
Author:
Heng Pan
Author:
Adam Giza
Author:
Gulnara Akylzhanova
Author:
Karlheinz Holzmann
Author:
Annika Scheffold
Author:
Harvey E. Johnston
Author:
Ru-Fang Yeh
Author:
Tetyana Klymenko
Author:
Barbara Eichorst
Author:
Lars Bullinger
Author:
Kirsten Fischer
Author:
Martin Weisser Weisser
Author:
Tadeusz Robak
Author:
Christof Schneider
Author:
John Gribben
Author:
Lekh N Dahal
Author:
Matthew J. Carter
Author:
Oliver Elemento
Author:
Dan A. Landau
Author:
Donna S. Neuberg
Author:
Mark S. Cragg
Author:
Axel Benner
Author:
Michael Hallek
Author:
Catherine J Wu
Author:
Hartmut Dohner
Author:
Stephan Stilgenbauer
Author:
Daniel Mertens
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