Altered metabolism with increased glycolysis has been established as a fundamental mechanism to support biosynthesis in cancer cells in a metabolic program termed aerobic glycolysis. 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. These cells, however, are short-lived. Oncogenic Notch is tightly associated with T cell Acute Lymphoblastic Leukemia (T-ALL) and we made the surprising finding that while Notch-driven T-ALL cells use aerobic glycolysis; they do so at a much lower rate than normally stimulated but short-lived effectors T cells. Thus, T-ALL cells utilize aerobic glycolysis to suppot proliferation, but do not achieve their maximal metabolic capacity. We propose here that 5'AMP Activated Protein Kinase (AMPK) plays dual roles in T-ALL cells to balance the biosynthetic benefits of aerobic glycolysis against the stress of overly deregulated metabolism that may impair cell proliferation or viability. Notch induces Myc and activates the Phosphotidyl- inositide 3-Kinase (PI3K)/Akt/mTOR signaling pathway that can drive aerobic glycolysis. However, mTOR complex 1 (mTORC1) signaling was impaired and our metabolomic analyses showed T-ALL cells had surprisingly low levels of intracellular ATP and ratio of ATP/AMP. T-ALL cells were also significantly more sensitive to metabolic inhibitors than resting or activated T cells. These data suggest Notch-induced metabolic stress, and we found that AMPK was activated in primary T-ALL and T-ALL cell lines. Genetic deletion of AMPK (AMPK?1) in vivo increased mTORC1 signaling and aerobic glycolysis, yet also led to a rapid loss of T-ALL cells. Thus while slowing cell growth by inhibiting mTORC1, AMPK also is essential for T-ALL cells. Our long-term objectives are to better understand metabolic vulnerabilities of T-ALL and identify mechanisms by which AMPK is essential to regulate T-ALL proliferation and survival. To achieve these goals we will test the hypothesis Notch leads to mitochondrial deregulation and that AMPK activity is essential to regulate T-ALL cell metabolic and longevity. We propose to (1) Test the effects of direct modulation of glucose or mitochondrial 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 how AMPK provides both a metabolic brake on mTORC1 and promotes mitochondrial metabolism to prevent apoptosis. Together these studies that are based on both normal and leukemic T cell metabolism show a dual role for AMPK that will provide understanding of T-ALL metabolism in a new model of metabolic regulation of cell fate via AMPK.

Public Health Relevance

Degregulated cell metabolism may provide a new opportunity to treat cancer. Our studies comparing normal and leukemic T cells have suggested that metabolic activity must be balanced to support 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 #
1R21CA194829-01A1
Application #
9022984
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Jhappan, Chamelli
Project Start
2015-12-01
Project End
2016-04-29
Budget Start
2015-12-01
Budget End
2016-04-29
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pathology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37240
Beckermann, Kathryn E; Dudzinski, Stephanie O; Rathmell, Jeffrey C (2017) Dysfunctional T cell metabolism in the tumor microenvironment. Cytokine Growth Factor Rev 35:7-14
Andrejeva, Gabriela; Rathmell, Jeffrey C (2017) Similarities and Distinctions of Cancer and Immune Metabolism in Inflammation and Tumors. Cell Metab 26:49-70
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
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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