Targeting metabolic reprogramming in chronic lymphocytic leukemia

Abstract

Metabolic reprogramming, fundamentally pivotal in carcinogenesis and progression of cancer, is considered as a promising therapeutic target against tumors. In chronic lymphocytic leukemia (CLL) cells, metabolic abnormalities mediate alternations in proliferation and survival compared with normal B cells. However, the role of metabolic reprogramming is still under investigation in CLL. In this review, the critical metabolic processes of CLL were summarized, particularly glycolysis, lipid metabolism and oxidative phosphorylation. The effects of T cells and stromal cells in the microenvironment on metabolism of CLL were also elucidated. Besides, the metabolic alternation is regulated by some oncogenes and tumor suppressor regulators, especially TP53, MYC and ATM. Thus, the agents targeting metabolic enzymes or signal pathways may impede the progression of CLL. Both the inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) statins and the lipoprotein lipase inhibitor orlistat induce the apoptosis of CLL cells. In addition, a series of oxidative phosphorylation inhibitors play important roles in decreasing the proliferation of CLL cells. We epitomized recent advancements in metabolic reprogramming in CLL and discussed their clinical potentiality for innovative therapy options. Metabolic reprogramming plays a vital role in the initiation and progression of CLL. Therapeutic approaches targeting metabolism have their advantages in improving the survival of CLL patients. This review may shed novel light on the metabolism of CLL, leading to the development of targeted agents based on the reshaping metabolism of CLL cells.

Keywords: Chronic lymphocytic leukemia; Lipid metabolism; Metabolism reprogramming; Targeted therapy.

Fig. 1

Metabolic reprogramming in chronic lymphocytic leukemia (CLL). In CLL cells, aerobic glycolysis, lipid synthesis, reductive carboxylation, beta-oxidation of fatty acids, and the consumption of glutamine are upregulated. These changes benefit CLL cells as they satisfy their demands of proliferation. CLL chronic lymphocytic leukemia, GLUT glucose transporter, G6P glucose 6-phosphate, TIGAR TP53-induced glycolysis and apoptosis regulator, TCA tricarboxylic acid, TG triglyceride, LPL lipoprotein lipase, LCFA-CoAs long-chain fatty acyl coenzyme A, HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A, HMGCR 3-hydroxy-3-methylglutaryl coenzyme A reductase, FFA free fatty acid, ApoA apolipoprotein A, CPT carnitine palmitoyl transferases, α-KG α-ketoglutarate, CAT-1 cationic amino acid transporter-1, STIM1 stromal interaction molecule 1, ROS reactive oxygen species

Fig. 2

Aerobic glycolysis in CLL cells. A In normal cells, glucose is converted to pyruvate, which feeds the tricarboxylic acid (TCA) cycle for energy production under normoxia; B Pyruvate predominantly produces energy by lactic acid fermentation, even in the presence of oxygen (aerobic glycolysis) in cancer cells. The flux of pyruvate entering TCA cycle is decreased. C CLL cells do not follow the Warburg effect. They are not primarily dependent on glycolysis to produce energy, but increasing mitochondrial oxidative phosphorylation (OXPHOS). TCA tricarboxylic acid, OXPHOS oxidative phosphorylation