AMPK Protects Leukemia-Initiating Cells in Myeloid Leukemias from Metabolic Stress in the Bone Marrow

Abstract

SUMMARY How cancer cells adapt to metabolically adverse conditions in patients and strive to proliferate is a fundamental question in cancer biology. Here we show that AMP-activated protein kinase (AMPK), a metabolic checkpoint kinase, confers metabolic stress resistance to leukemia-initiating cells (LICs) and promotes leukemogenesis. Upon dietary restriction, MLL-AF9-induced murine AML activated AMPK and maintained leukemogenic potential. AMPK deletion significantly delayed leukemogenesis and depleted LICs by reducing the expression of glucose transporter 1 (Glut1), compromising glucose flux, and increasing oxidative stress and DNA damage. LICs were particularly dependent on AMPK to suppress oxidative stress in the hypoglycemic bone marrow environment. Strikingly, AMPK inhibition synergized with physiological metabolic stress caused by dietary restriction and profoundly suppressed leukemogenesis. Our results indicate that AMPK protects LICs from metabolic stress, and that combining AMPK inhibition with physiological metabolic stress potently suppresses AML by inducing oxidative stress and DNA damage.

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

“…AMPK has previously been shown to suppress aerobic glycolysis and progression of B cell leukemia through the inhibition of HIF1α (Faubert et al, 2013). Recent work has also indicated AMPK was necessary to maintain AML tumor initiating cell viability under conditions of metabolic stress through promoting the expression of Glut1 (Saito et al, 2015). We show AMPK acts in T-ALL to negatively regulate aerobic glycolysis and Glut1 while also maintaining mitochondrial function to promote cell survival.…”

“…Conversely, multiple oncogenic signals, including oncogenic Ras and Myc, can generate metabolic stress (Liu et al, 2012; Moiseeva et al, 2009), and AMPK may promote cancer cell survival under such conditions. Indeed, LKB1 loss sensitizes to metabolic stress(Shackelford et al, 2013) and AMPK may be important to mitigate metabolic stress in myeloid leukemia initiating cells(Saito et al, 2015) and activated T cells in vivo (Blagih et al, 2015). …”

Sorting protein VPS33B regulates exosomal autocrine signaling to mediate hematopoiesis and leukemogenesis

“…Because VPS33B has been reported to be a regulator of MVB maturation (22,27,28), we speculated that secretory proteins may be associated with VPS33B. Therefore, we examined the colocalization of VPS33B and several groups of candidate proteins known to be critical for HSC stemness (TPO, ANGPTL2, ANGPTL3, LDHA, and PKM2) (8,14,15,34,35) as well as other potential HSC stemness regulators (GLUT1 and other members of the ANGPTL family) (34,36) using immunofluorescence staining. Indeed, we demonstrated that ectopically expressed TPO, ANGPTL2, and ANGPTL3 colocalized with VPS33B in 293T cells (Figure 2A and Supplemental Figure 1E).…”

SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation

“…Recent evidence revealed that leukaemia cells exhibited an increased dependence on aerobic glycolysis67. Mouse model studies further demonstrated that enhanced glucose uptake accelerated leukemogenesis in vivo 8910. Besides, glycolysis inhibition resulted in growth arrest or cell death of AML cells, and sensitized leukaemia cells to chemotherapeutic agents711.…”