Dysregulation of cancer cell bioenergetics is one of the hallmarks of cancer. The Warburg effect is one such documented change. However, glucose metabolism is not universally increased in cancer cells. Uptake of 18F-FDG in chronic lymphocytic leukemia (CLL), the most common incurable malignancy of B-cells, fails as a marker of proliferation and whilst the underlying reason is poorly understood it suggests that CLL cells utilize energy sources other than glucose to proliferate. Using a combination of genetic, proteomic and lipidomic analyses, complemented with microscopy and nutrient uptake assays the preferred metabolic pathways of CLL cells have been identified. In a variety of nutrient deprived cell lines we measured the uptake of fluorescently labelled short, medium and long-chain fatty acids and the glucose analog 2-NBDG by flow cytometry. The two CLL lines, MEC1 and MEC2 have a preference for long chain fatty acid uptake (LCFA), over short and medium chain and low uptake of 2-NBDG. We found an increase in the LCFA uptake receptor, CD36, in primary CLL samples and found that the expression of GLUT1 and GLUT3 were similar in CLL samples compared to healthy B-cells.
The data taken from our proteomic studies found an upregulation of proteins involved in lipogenesis in CLL peripheral blood lymphocytes, which are often quiescent and an increase in β-oxidation proteins in the proliferative compartment of the lymph node. These findings together with our morphological examination of CLL cells using transmission electron microscopy and confocal microscopy suggests that peripheral CLL cells scavenge lipids, which are stored in lipid droplets and are protected from degradation by a high expression of PLIN proteins. These cells circulate back to the lymph nodes to proliferate, the lipid droplets are degraded, likely by lipophagy and neutral lipolysis which frees fatty acids for β-oxidation. Our results begin to unravel CLL bioenergetics and dysregulation of cellular metabolism that occurs in this disease. We are now investigating whether the manipulation of these pathways, particularly lipophagy, may represent a novel therapeutic approach in CLL.