Abstract C155: Targeting glucose metabolism to suppress Ph+B-ALL progression.

Abstract

Abstract Philadelphia chromosome positive B cell derived acute lymphoblastic leukemia (Ph+B-ALL) is a type of aggressive leukemia that lacks effective treatment. The high glucose metabolism observed in many other cancers suggests that targeting glucose metabolism may provide a novel therapeutic approach for Ph+B-ALL. However, metabolic features of Ph+B-ALL and metabolic stress responses have not been described. In this study, we examined human primary B-ALL samples, B-ALL cell lines and primary murine Ph+B-ALL to identify metabolic program and metabolic stress responses of Ph+B-ALL cells. Metabolic measurements of extracellular flux and glucose consumption showed that B-ALL cell lines are highly glycolytic and preferentially utilize glucose. Consistent with a dependence on elevated glycolysis, primary human B-ALL cells were more sensitive than normal B cells to inhibition of glycolysis with 2-deoxyglucose (2-DG). This metabolic stress induced cell death was likely to be mediated through p53 and Bcl-2 family proteins. 2-DG treatment induced expression of pro-apoptotic Bcl-2 family protein Bim and primary murine Ph+B-ALL cells generated from p53-/- or Bim-/- background remained viable even when treated with 2-DG. To specifically investigate how inhibition of glucose metabolism impacts B-ALL survival and disease progression in vivo with genetic tools, we generated murine Ph+ B-ALL cells on a Glut1fl/fl Ubi-CreER background that allow specific deletion of Glut1 in cancer cells upon treatment of tamoxifen. In vitro deletion of Glut1 reduced glucose uptake and glucose metabolism, although glycolysis was not wholly suppressed. This partial reduction of glucose metabolism led to greatly reduced cell proliferation and some cell death in vitro. Importantly, in vivo deletion of Glut1 after transfer of B-ALL cells into congenic recipients suppressed B-ALL progression and prolonged animal survival. These data show that B-ALL cells exhibit high glucose metabolism similar to other types of cancer and are sensitive to glucose metabolism inhibition. Reduction of glucose metabolism can impede B-ALL proliferation or cause cell death through p53 and Bim and thus suppress B-ALL progression in vivo. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C155. Citation Format: Tingyu Liu, Handan Xiang, Amanda Nichols, Valerie Gerriets, Rigel Kishton, David Rizzieri, Jeffrey C. Rathmell. Targeting glucose metabolism to suppress Ph+B-ALL progression. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C155.