Altered metabolism with increased glycolysis in a metabolic program termed aerobic glycolysis has been established as a fundamental mechanism to support biosynthesis of cancer cells. It is now apparent, however, that normal cells can also use this pathway to support growth and proliferation. We have shown that normal T cells induce aerobic glycolysis upon activation as they transition from quiescence to become highly proliferative but short-lived effectors. Comparing metabolic and signaling events in T cell Acute Lymphoblastic Leukemia (T-ALL) with normal T cell activation led to the surprising finding that while cancer cells are considered highly glycolytic and T-ALL cells use aerobic glycolysis; they do so at a much lower rate than normal stimulated T cells. Thus, T-ALL cells utilize aerobic glycolysis at a sufficient rate to support proliferation, but do not achieve the rates of short-livd effector T cells. We propose that T-ALL cells balance the biosynthetic benefits of aerobic glycolysis against the stress of overly deregulated metabolism that leads to apoptosis of activated T cells. The Phosphotidylinositide 3-Kinase (PI3K)/Akt/mTOR and 5'AMP Protein Kinase (AMPK) signaling pathways may control this metabolic balance, as the PI3K/Akt/mTOR pathway promotes aerobic glycolysis and is oncogenic while AMPK suppresses this pathway and can suppress tumorigenesis. Paradoxically, however, constitutive activation of PI3K was recently associated with reduced T cell numbers and immunodeficiency. Further, we show here that constitutively high Akt activity increases ROS and cell death in leukemia. Unexpectedly, we found AMPK to be activated in T-ALL cells and this may restrain excessive PI3K/Akt/mTOR and aerobic glycolysis. Thus while slowing cell growth, AMPK may also promote T-ALL cell survival. Inactivation of AMPK, however, may release PI3K/Akt/mTOR and excessive glycolytic metabolism to prevent control of ROS and lead to apoptosis. Our long-term objectives are to better understand metabolic vulnerabilities of T-ALL and identify mechanisms that may allow metabolic reprogramming of T-ALL cells to enter short-lived states similar to activated T cells. To achieve these goals we will test the hypothesis that elevated glycolysis via Akt promotes ROS and a short-lifespan for leukemic cells, but is held in check by AMPK. We propose to (1) Test the effects of direct modulation of glucose metabolism on the leukemic progression and cell lifespan of primary T-ALL and (2) Determine how AMPK regulates T- ALL progression and metabolism to test if AMPK provides a metabolic brake that prevents T-ALL apoptosis. Together these studies based on comparison of normal and leukemic T cell metabolism will provide new understanding of T-ALL metabolism and test a new model of T-ALL cell fate that may be applicable to a wide range of glycolytic cancers.

Public Health Relevance

Degregulated cell metabolism may provide a new approach to treat cancer. Our studies comparing normal and leukemic T cells have suggested a metabolic balance is essential for cellular longevity and cancer progression. We will test the role of cell metabolism in regulating T cell Acute Lymphoblastic Leukemia to determine if modifying this metabolic balance will provide a new approach to enhance metabolic stress and promote cancer cell death.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
6R21CA194829-02
Application #
9248521
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Jhappan, Chamelli
Project Start
2015-12-01
Project End
2017-11-30
Budget Start
2016-04-30
Budget End
2016-11-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
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Andrejeva, Gabriela; Rathmell, Jeffrey C (2017) Similarities and Distinctions of Cancer and Immune Metabolism in Inflammation and Tumors. Cell Metab 26:49-70
Hosios, Aaron M; Hecht, Vivian C; Danai, Laura V et al. (2016) Amino Acids Rather than Glucose Account for the Majority of Cell Mass in Proliferating Mammalian Cells. Dev Cell 36:540-9
Johnson, Marc O; Siska, Peter J; Contreras, Diana C et al. (2016) Nutrients and the microenvironment to feed a T cell army. Semin Immunol 28:505-513
Kishton, Rigel J; Barnes, Carson E; Nichols, Amanda G et al. (2016) AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival. Cell Metab 23:649-62
O'Neill, Luke A J; Kishton, Rigel J; Rathmell, Jeff (2016) A guide to immunometabolism for immunologists. Nat Rev Immunol 16:553-65