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Primary effusion lymphoma (PEL) is a rare and aggressive B-cell lymphoma with a dismal prognosis caused by infection of Kaposi's sarcoma-associated herpesvirus. Despite the findings that numerous viral genes and cellular pathways are essential for the proliferation and survival of PEL cells, there is currently no effective therapeutic treatment for PEL. Here, we report that the metabolic sensor SIRT1 is functionally required for sustaining the proliferation and survival of PEL cells. Knockdown of SIRT1 with specific shRNAs or inhibition of SIRT1 with an inhibitor (tenovin-6) induced cell cycle arrest and apoptosis in PEL cells. We detected high levels of AMPK activation in PEL cells, reflected in AMPKα1 phosphorylation at T174. Knockdown or inhibition of SIRT1 reduced AMPK activation, indicating that SIRT1 was required for AMPK activation. Interestingly, knockdown of AMPK with specific shRNAs or inhibition of AMPK with the inhibitor compound C recapitulated the phenotype of SIRT1, and induced cell cycle arrest and apoptosis, whereas overexpression of a constitutively active AMPK construct rescued the cytotoxic effect of SIRT1 knockdown. Remarkably, treatment with tenovin-6 effectively inhibited the initiation and progression of PEL, and significantly extended the survival of mice in a murine PEL model. Taken together, these results illustrate that the SIRT1-AMPK axis is essential for maintaining the proliferation and survival of PEL and identify SIRT1 and AMPK as potential therapeutic targets, and tenovin-6 as a candidate therapeutic agent for PEL patients. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)