Multi-omics reveals clinically relevant proliferative drive associated with mTOR-MYC-OXPHOS activity in chronic lymphocytic leukemia
| Autor: | Sascha Dietrich, Brian Giacopelli, Jennifer Hüllein, Christopher C. Oakes, Bernd Bodenmiller, Lena Wagner, Almut Lütge, Ferran Nadeu, Ester Cannizzaro, Julio Delgado, Wolfgang Huber, Fabienne Meier-Abt, Thorsten Zenz, Sebastian Scheinost, Dimitrios Mougiakakos, Maurizio Mangolini, Andrea Jacobs, Junyan Lu, Holly A. R. Giles, Elias Campo, Peter-Martin Bruch, Martin Böttcher, Ingo Ringshausen |
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| Přispěvatelé: | University of Zurich, Zenz, Thorsten, Huber, Wolfgang |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Proteomics
Cancer Research Chronic lymphocytic leukemia Lymphocyte Cell 610 Medicine & health Biology Oxidative Phosphorylation Article Transcriptome hemic and lymphatic diseases medicine Humans Doubling time Clinical significance 1306 Cancer Research PI3K/AKT/mTOR pathway TOR Serine-Threonine Kinases DNA Methylation medicine.disease Leukemia Lymphocytic Chronic B-Cell medicine.anatomical_structure Oncology DNA methylation 10032 Clinic for Oncology and Hematology Cancer research 2730 Oncology 11493 Department of Quantitative Biomedicine |
| Zdroj: | Nature Cancer, 2 (8) Nat Cancer |
| Popis: | Chronic Lymphocytic Leukemia (CLL) has a complex pattern of driver mutations and much of its clinical diversity remains unexplained. We devised a method for simultaneous subgroup discovery across multiple data types and applied it to genomic, transcriptomic, DNA methylation and ex-vivo drug response data from 217 Chronic Lymphocytic Leukemia (CLL) cases. We uncovered a biological axis of heterogeneity strongly associated with clinical behavior and orthogonal to the known biomarkers. We validated its presence and clinical relevance in four independent cohorts (n=547 patients). We find that this axis captures the proliferative drive (PD) of CLL cells, as it associates with lymphocyte doubling rate, global hypomethylation, accumulation of driver aberrations and response to pro-proliferative stimuli. CLL-PD was linked to the activation of mTOR-MYC-oxidative phosphorylation (OXPHOS) through transcriptomic, proteomic and single cell resolution analysis. CLL-PD is a key determinant of disease outcome in CLL. Our multi-table integration approach may be applicable to other tumors whose inter-individual differences are currently unexplained. |
| Databáze: | OpenAIRE |
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