| Literature DB >> 34423310 |
Junyan Lu1,2, Ester Cannizzaro3, Fabienne Meier-Abt3, Sebastian Scheinost4, Peter-Martin Bruch4,5,6, Holly Ar Giles1,2, Almut Lütge7, Jennifer Hüllein1,4, Lena Wagner4, Brian Giacopelli8, Ferran Nadeu9,10, Julio Delgado10,11, Elías Campo9,10,11, Maurizio Mangolini12, Ingo Ringshausen12, Martin Böttcher13, Dimitrios Mougiakakos13, Andrea Jacobs14, Bernd Bodenmiller14, Sascha Dietrich2,5,6,15, Christopher C Oakes8,16, Thorsten Zenz3,4, Wolfgang Huber1,2.
Abstract
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.Entities:
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Year: 2021 PMID： 34423310 PMCID： PMC7611543 DOI： 10.1038/s43018-021-00216-6
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347