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

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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). [Article]

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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.

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Official URL:

https://www.nature.com/articles/s41467-021-25403-y

Open Access URL:

https://www.nature.com/articles/s41467-021-25403-y...

Open Access Version:

Published version

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

Event Location:

England

Identifiers

Identification Number:

10.1038/s41467-021-25403-y

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Article

SWORD Depositor:

Symplectic Elements

Depositing User:

Symplectic Elements