Metabolic plasticity in CLL: adaptation to the hypoxic niche

TY - JOUR

T1 - Metabolic plasticity in CLL: adaptation to the hypoxic niche

AU - Koczula, K M

AU - Ludwig, C

AU - Hayden, R

AU - Cronin, L

AU - Pratt, Guy

AU - Parry, H

AU - Tennant, D

AU - Drayson, M

AU - Bunce, C M

AU - Khanim, F L

AU - Günther, U L

PY - 2016/1

Y1 - 2016/1

N2 - Metabolic transformation in cancer is increasingly well understood. However, little is known about the metabolic responses of cancer cells that permit their survival in different microenvironments. We have used a nuclear magnetic resonance based approach to monitor metabolism in living primary CLL cells and to interrogate their real-time metabolic responses to hypoxia. Our studies demonstrate considerable metabolic plasticity in CLL cells. Despite being in oxygenated blood, circulating CLL cells are primed for hypoxia as measured by constitutively low level HIF-1α activity and modest lactate production from glycolysis. Upon entry to hypoxia we observed rapid upregulation of metabolic rates. CLL cells that had adapted to hypoxia returned to the 'primed' state when re-oxygenated and again showed the same adaptive response upon secondary exposure to hypoxia. We also observed HIF-1α independent differential utilization of pyruvate in oxygenated and hypoxic conditions. When oxygenated, CLL cells released pyruvate, but in hypoxia imported pyruvate to protect against hypoxia-associated oxidative stress. Finally we identified a marked association of slower resting glucose and glutamine consumption, and lower alanine and lactate production with Binet A0 stage samples indicating that CLL may be divided into tumors with higher and lower metabolic states that reflect disease stage.Leukemia accepted article preview online, 23 July 2015. doi:10.1038/leu.2015.187.

AB - Metabolic transformation in cancer is increasingly well understood. However, little is known about the metabolic responses of cancer cells that permit their survival in different microenvironments. We have used a nuclear magnetic resonance based approach to monitor metabolism in living primary CLL cells and to interrogate their real-time metabolic responses to hypoxia. Our studies demonstrate considerable metabolic plasticity in CLL cells. Despite being in oxygenated blood, circulating CLL cells are primed for hypoxia as measured by constitutively low level HIF-1α activity and modest lactate production from glycolysis. Upon entry to hypoxia we observed rapid upregulation of metabolic rates. CLL cells that had adapted to hypoxia returned to the 'primed' state when re-oxygenated and again showed the same adaptive response upon secondary exposure to hypoxia. We also observed HIF-1α independent differential utilization of pyruvate in oxygenated and hypoxic conditions. When oxygenated, CLL cells released pyruvate, but in hypoxia imported pyruvate to protect against hypoxia-associated oxidative stress. Finally we identified a marked association of slower resting glucose and glutamine consumption, and lower alanine and lactate production with Binet A0 stage samples indicating that CLL may be divided into tumors with higher and lower metabolic states that reflect disease stage.Leukemia accepted article preview online, 23 July 2015. doi:10.1038/leu.2015.187.

U2 - 10.1038/leu.2015.187

DO - 10.1038/leu.2015.187

M3 - Article

C2 - 26202928

VL - 30

SP - 65

EP - 73

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 1

ER -