TP53-Induced Glycolysis and Apoptosis Regulator Protects from Spontaneous Apoptosis and Predicts Poor Prognosis in Chronic Lymphocytic Leukemia

The circulating chronic lymphocytic leukemia (CLL) cells appear not to be overly utilizing aerobic glycolysis. However, CLL cells' recurrent contact with the stromal microenvironment leads to an increase of aerobic glycolysis and the cells' overall glycolytic capacity, which promotes cell survival and proliferation. TP53-induced glycolysis and apoptosis regulator (TIGAR) has been directly implicated in cellular metabolism in the control of glycolysis. TIGAR inhibits glycolysis and protects cells from intracellular reactive oxygen species (ROS)-associated apoptosis. Here, we investigated correlation between TIGAR expression and apoptosis in CLL primary cells, along with its relationship with the clinical characteristics and prognosis in 102 newly diagnosed CLL patients. Our data showed TIGARoverexpression correlated with protection from spontaneous apoptosis in CLL cells, and is strongly associated with advanced Binet stage, unmutated immunoglobulin heavy-chain variable region (IGHV) status, CD38 positivity, β2-microglobulin and p53 aberrations. Higher expression of TIGAR was associated with briefer treatment-free survival (median: 3 months vs. 51 months, p = 0.0108) and worse overall survival (median: 74 months vs. not reached, p = 0.0242), as well as their diverse responses to fludarabine based chemotherapy. TIGAR expression of the patients who were resistant to chemotherapy was significantly higher than those who were sensitive to chemotherapy (mean: 0.3859±0.1710 vs. 0.0974±0.0291, p = 0.0290). Taken together, our findings depict how bioenergetics characteristics could be therapeutically exploited in CLL.