AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control T-ALL Cell Stress and Survival

作者：Kishton Rigel J; Barnes Carson E; Nichols Amanda G; Cohen Sivan; Gerriets Valerie A; Siska Peter J; Macintyre Andrew N; Goraksha Hicks Pankuri; de Cubas Aguirre A; Liu Tingyu; Warmoes Marc O; Abel E Dale; Yeoh Allen Eng Juh; Gershon Timothy R; Rathmell W Kimryn; Richards Kristy L; Locasale Jason W; Rathmell Jeffrey C^*

来源：Cell Metabolism, 2016, 23(4): 649-662.

DOI：10.1016/j.cmet.2016.03.008

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy associated with Notch pathway mutations. While both normal activated and leukemic T cells can utilize aerobic glycolysis to support proliferation, it is unclear to what extent these cell populations are metabolically similar and if differences reveal T-ALL vulnerabilities. Here we show that aerobic glycolysis is surprisingly less active in T-ALL cells than proliferating normal T cells and that T-ALL cells are metabolically distinct. Oncogenic Notch promoted glycolysis but also induced metabolic stress that activated 5' AMP-activated kinase (AMPK). Unlike stimulated T cells, AMPK actively restrained aerobic glycolysis in T-ALL cells through inhibition of mTORC1 while promoting oxidative metabolism and mitochondrial Complex I activity. Importantly, AMPK deficiency or inhibition of Complex I led to T-ALL cell death and reduced disease burden. Thus, AMPK simultaneously inhibits anabolic growth signaling and is essential to promote mitochondrial pathways that mitigate metabolic stress and apoptosis in T-ALL.

• 出版日期2016-4-12