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, Tetyana, 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. (2021). Multi-platform profiling characterizes molecular subgroups and resistance networks in chronic lymphocytic leukemia. Nature Communications, 12 (1).

Preview

PDF Nat Comm published.pdf - Published Version Creative Commons Attribution. Download (5MB) | Preview

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.

Item Type:	Article
Uncontrolled Keywords:	Ataxia Telangiectasia Mutated Proteins; Chromosome Aberrations; DNA Damage; DNA Repair; Epithelial-Mesenchymal Transition; Gene Expression Profiling; Gene Expression Regulation, Leukemic; Gene Regulatory Networks; Genomic Instability; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Polymorphism, Single Nucleotide; Shelterin Complex; Telomere-Binding Proteins; Tumor Suppressor Protein p53; Humans; DNA Damage; Chromosome Aberrations; Genomic Instability; Telomere-Binding Proteins; Gene Expression Profiling; DNA Repair; Gene Expression Regulation, Leukemic; Mutation; Polymorphism, Single Nucleotide; Tumor Suppressor Protein p53; Gene Regulatory Networks; Leukemia, Lymphocytic, Chronic, B-Cell; Epithelial-Mesenchymal Transition; Ataxia Telangiectasia Mutated Proteins; Shelterin Complex
Identification Number:	https://doi.org/10.1038/s41467-021-25403-y
SWORD Depositor:	Symplectic Elements
Depositing User:	Symplectic Elements
Date Deposited:	11 Mar 2022 16:06
Last Modified:	11 Mar 2022 16:15
URI:	https://shura.shu.ac.uk/id/eprint/29876

Actions (login required)

View Item

Downloads

Publication Metrics