Co-activation of AMPK and mTORC1 Induces Cytotoxicity in Acute Myeloid Leukemia

• AMPK activation blocks AML propagation without toxicity to normal hematopoiesis
• Cytotoxicity induced by an AMPK activator (GSK621) involves autophagy in AML
• Co-activation of AMPK and mTORC1 is synthetically lethal in AML
• AMPK and mTORC1 crosstalk requires eIF2α/ATF4 signaling

SummaryAMPK is a master regulator of cellular metabolism that exerts either oncogenic or tumor suppressor activity depending on context. Here, we report that the specific AMPK agonist GSK621 selectively kills acute myeloid leukemia (AML) cells but spares normal hematopoietic progenitors. This differential sensitivity results from a unique synthetic lethal interaction involving concurrent activation of AMPK and mTORC1. Strikingly, the lethality of GSK621 in primary AML cells and AML cell lines is abrogated by chemical or genetic ablation of mTORC1 signaling. The same synthetic lethality between AMPK and mTORC1 activation is established in CD34-positive hematopoietic progenitors by constitutive activation of AKT or enhanced in AML cells by deletion of TSC2. Finally, cytotoxicity in AML cells from GSK621 involves the eIF2α/ATF4 signaling pathway that specifically results from mTORC1 activation. AMPK activation may represent a therapeutic opportunity in mTORC1-overactivated cancers.

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