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Ferrata Storti Foundation
Haematologica 2019 Volume 104(9):1830-1840
Chronic Lymphocytic Leukemia
Energy metabolism is co-determined
by genetic variants in chronic lymphocytic leukemia and influences drug sensitivity
Junyan Lu,1* Martin Böttcher,2* Tatjana Walther,3 Dimitrios Mougiakakos,2 Thorsten Zenz3,4 and Wolfgang Huber1
1European Molecular Biology Laboratory (EMBL), Heidelberg, Germany; 2Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Erlangen, Germany; 3Molecular Therapy in Hematology and Oncology, National Center for Tumor Diseases and German Cancer Research Centre, Heidelberg, Germany and
Department of Medical Oncology and Hematology, University Hospital Zürich and
4
University of Zürich, Zürich, Switzerland
*JL and MB contributed equally to this work.
ABSTRACT
Chronic lymphocytic leukemia cells have an altered energy metab- olism compared to normal B cells. While there is a growing understanding of the molecular heterogeneity of the disease, the extent of metabolic heterogeneity and its relation to molecular hetero- geneity has not been systematically studied. Here, we assessed 11 bioen- ergetic features, primarily reflecting cell oxidative phosphorylation and glycolytic activity, in leukemic cells from 140 chronic lymphocytic leukemia patients using metabolic flux analysis. We examined these bioenergetic features for relationships with molecular profiles (including genetic aberrations, transcriptome and methylome profiles) of the tumors, their ex vivo responses to a panel of 63 compounds, and with clinical data. We observed that leukemic cells with mutated immunoglobulin variable heavy-chain show significantly lower gly- colytic activity than cells with unmutated immunoglobulin variable heavy-chain. Accordingly, several key glycolytic genes (PFKP, PGAM1 and PGK1) were found to be down-regulated in samples harboring mutated immunoglobulin variable heavy-chain. In addition, 8q24 copy number gains, 8p12 deletions, 13q14 deletions and ATM mutations were identified as determinants of cellular respiration. The metabolic state of leukemic cells was associated with drug sensitivity; in particular, higher glycolytic activity was linked to increased resistance towards several drugs including rotenone, navitoclax, and orlistat. In addition, we found glycolytic capacity and glycolytic reserve to be predictors of overall sur- vival (P<0.05) independently of established genetic predictors. Taken together, our study shows that heterogeneity in the energy metabolism of chronic lymphocytic leukemia cells is influenced by genetic variants and this could be therapeutically exploited in the selection of therapeutic strategies.
Introduction
Resistance to apoptosis rather than aberrant proliferation is regarded as the rea- son for chronic lymphocytic leukemia (CLL) cell accumulation. However, active proliferation also contributes to CLL pathogenesis, as sizable clonal birth rates were observed in this disease.1,2 This suggests a substantial bioenergetic demand for proliferating subsets of CLL cells in order to support cell growth and division. Deregulated energy metabolism is considered to be one of the hallmarks of cancer.3 While molecular mechanisms promoting survival and proliferation of CLL cells have been extensively studied, fewer studies have addressed energy metabolism in CLL. Garcia-Manteiga et al. suggested oxidative phosphorylation as the primary
Correspondence:
WOLFGANG HUBER
wolfgang.huber@embl.de
THORSTEN ZENZ
thorsten.zenz@usz.ch
DIMITRIOS MOUGIAKAKOS
dimitrios.mougiakakos@uk-erlangen.de
Received: July 30, 2018. Accepted: February 14, 2019. Pre-published: February 21, 2019.
doi:10.3324/haematol.2018.203067
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/9/1830
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