Forced expression of the DEK-NUP214 fusion protein promotes proliferation dependent on upregulation of mTOR.
BACKGROUND
The t(6;9)(p23;q34) chromosomal translocation is found in 1% of acute myeloid leukemia and encodes the fusion protein DEK-NUP214 (formerly DEK-CAN) with largely uncharacterized functions.


METHODS
We expressed DEK-NUP214 in the myeloid cell lines U937 and PL-21 and studied the effects on cellular functions.


RESULTS
In this study, we demonstrate that expression of DEK-NUP214 increases cellular proliferation. Western blot analysis revealed elevated levels of one of the key proteins regulating proliferation, the mechanistic target of rapamycin, mTOR. This conferred increased mTORC1 but not mTORC2 activity, as determined by the phosphorylation of their substrates, p70 S6 kinase and Akt. The functional importance of the mTOR upregulation was determined by assaying the downstream cellular processes; protein synthesis and glucose metabolism. A global translation assay revealed a substantial increase in the translation rate and a metabolic assay detected a shift from glycolysis to oxidative phosphorylation, as determined by a reduction in lactate production without a concomitant decrease in glucose consumption. Both these effects are in concordance with increased mTORC1 activity. Treatment with the mTORC1 inhibitor everolimus (RAD001) selectively reversed the DEK-NUP214-induced proliferation, demonstrating that the effect is mTOR-dependent.


CONCLUSIONS
Our study shows that the DEK-NUP214 fusion gene increases proliferation by upregulation of mTOR, suggesting that patients with leukemias carrying DEK-NUP214 may benefit from treatment with mTOR inhibitors.
Department of Hematology, Lund University, BMC B13, Klinikgatan 26, 221 84 Lund, Sweden. carl.sanden@med.lu.se.
Carl
C
Sandén
Malin
M
Ageberg
Jessica
J
Petersson
Andreas
A
Lennartsson
Urban
U
Gullberg
D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006019:Glycolysis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics* / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D010085:Oxidative Phosphorylation; D000075223:Poly-ADP-Ribose Binding Proteins; D014176:Protein Biosynthesis; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D020298:U937 Cells
D002868:Chromosomal Proteins, Non-Histone; C084738:DEK protein, human; C085914:NUP214 protein, human; D028861:Nuclear Pore Complex Proteins; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D000075223:Poly-ADP-Ribose Binding Proteins; D058570:TOR Serine-Threonine Kinases