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2016 ; 23
(4
): 649-62
Nephropedia Template TP
gab.com Text
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AMPK Is Essential to Balance Glycolysis and Mitochondrial Metabolism to Control
T-ALL Cell Stress and Survival
#MMPMID27076078
Kishton RJ
; Barnes CE
; Nichols AG
; Cohen S
; Gerriets VA
; Siska PJ
; Macintyre AN
; Goraksha-Hicks P
; de Cubas AA
; Liu T
; Warmoes MO
; Abel ED
; Yeoh AE
; Gershon TR
; Rathmell WK
; Richards KL
; Locasale JW
; Rathmell JC
Cell Metab
2016[Apr]; 23
(4
): 649-62
PMID27076078
show ga
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.