Energy metabolism is co-determined by genetic variants in chronic lymphocytic leukemia and influences drug sensitivity

Chronic lymphocytic leukemia cells have an altered energy metabolism 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 heterogeneity has not been systematically studied. Here, we assessed 11 bioenergetic 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 glycolytic 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 survival (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.