Multi-omics reveals clinically relevant proliferative drive associated with mTOR-MYC-OXPHOS activity in chronic lymphocytic leukemia

Lu J, Cannizzaro E, Meier-Abt F, Scheinost S, Bruch PM, Giles HAR, Lutge A, Huellein J, Wagner L, Giacopelli B, Nadeu F, Delgado J, Campo E, Mangolini M, Ringshausen I, Böttcher M, Mougiakakos D, Jacobs A, Bodenmiller B, Dietrich S, Oakes CC, Zenz T, Huber W (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Nature Cancer Springer Nature

DOI: 10.1038/s43018-021-00216-6

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 patients with CLL. We uncovered a biological axis of heterogeneity strongly associated with clinical behavior and orthogonal to known biomarkers. We validated its presence and clinical relevance in four independent cohorts (n = 547 patients). We found 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 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.

Authors with CRIS profile

Martin Böttcher Department of Medicine 5 – Haematology and Oncology Dimitrios Mougiakakos Professur für Hämatologie/Onkologie mit dem Schwerpunkt Tumorimmunologie

Involved external institutions

Eidgenössische Technische Hochschule Zürich (ETHZ) / Swiss Federal Institute of Technology in Zurich CH Switzerland (CH) University of Cambridge GB United Kingdom (GB) Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) ES Spain (ES) Centro de Investigación Biomédica en Red (CIBER) ES Spain (ES) Ohio State University US United States (USA) (US) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE) European Molecular Biology Laboratory (EMBL) DE Germany (DE) University of Zurich / Universität Zürich (UZH) CH Switzerland (CH) Universitätsspital Zürich (USZ) CH Switzerland (CH)

How to cite

APA:

Lu, J., Cannizzaro, E., Meier-Abt, F., Scheinost, S., Bruch, P.-M., Giles, H.A.R.,... Huber, W. (2021). Multi-omics reveals clinically relevant proliferative drive associated with mTOR-MYC-OXPHOS activity in chronic lymphocytic leukemia. Nature Cancer. https://doi.org/10.1038/s43018-021-00216-6

MLA:

Lu, Junyan, et al. "Multi-omics reveals clinically relevant proliferative drive associated with mTOR-MYC-OXPHOS activity in chronic lymphocytic leukemia." Nature Cancer (2021).

BibTeX: Download