The t(6;9)(p23;q34) chromosomal translocation is found in 1% of acute myeloid leukemia and\r\nencodes the fusion protein DEK-NUP214 (formerly DEK-CAN) with largely uncharacterized functions.\r\nMethods: We expressed DEK-NUP214 in the myeloid cell lines U937 and PL-21 and studied the effects on\r\ncellular functions.\r\nResults: In this study, we demonstrate that expression of DEK-NUP214 increases cellular proliferation. Western blot\r\nanalysis revealed elevated levels of one of the key proteins regulating proliferation, the mechanistic target of\r\nrapamycin, mTOR. This conferred increased mTORC1 but not mTORC2 activity, as determined by the\r\nphosphorylation of their substrates, p70 S6 kinase and Akt. The functional importance of the mTOR upregulation\r\nwas determined by assaying the downstream cellular processes; protein synthesis and glucose metabolism. A\r\nglobal translation assay revealed a substantial increase in the translation rate and a metabolic assay detected a shift\r\nfrom glycolysis to oxidative phosphorylation, as determined by a reduction in lactate production without a\r\nconcomitant decrease in glucose consumption. Both these effects are in concordance with increased mTORC1\r\nactivity. Treatment with the mTORC1 inhibitor everolimus (RAD001) selectively reversed the DEK-NUP214-induced\r\nproliferation, demonstrating that the effect is mTOR-dependent.\r\nConclusions: Our study shows that the DEK-NUP214 fusion gene increases proliferation by upregulation of\r\nmTOR, suggesting that patients with leukemias carrying DEK-NUP214 may benefit from treatment with\r\nmTOR inhibitors.
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