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Forced expression of the DEK-NUP214 fusion protein promotes proliferation dependent on upregulation of mTOR

Sandén, Carl LU ; Ageberg, Malin LU ; Petersson, Jessica LU ; Lennartsson, Andreas and Gullberg, Urban LU (2013) In BMC Cancer 13.
Abstract
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... (More)
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. (Less)
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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Acute myeloid leukemia, DEK-NUP214, DEK-CAN, Fusion gene, Proliferation, mTOR, Everolimus
in
BMC Cancer
volume
13
article number
440
publisher
BioMed Central (BMC)
external identifiers
  • wos:000325080000002
  • scopus:84884733616
  • pmid:24073922
ISSN
1471-2407
DOI
10.1186/1471-2407-13-440
language
English
LU publication?
yes
id
1ef0102d-d90f-4133-9750-e4125882bae4 (old id 4172540)
date added to LUP
2016-04-01 14:04:43
date last changed
2020-10-11 04:26:00
@article{1ef0102d-d90f-4133-9750-e4125882bae4,
  abstract     = {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.},
  author       = {Sandén, Carl and Ageberg, Malin and Petersson, Jessica and Lennartsson, Andreas and Gullberg, Urban},
  issn         = {1471-2407},
  language     = {eng},
  publisher    = {BioMed Central (BMC)},
  series       = {BMC Cancer},
  title        = {Forced expression of the DEK-NUP214 fusion protein promotes proliferation dependent on upregulation of mTOR},
  url          = {https://lup.lub.lu.se/search/ws/files/3763952/4253774},
  doi          = {10.1186/1471-2407-13-440},
  volume       = {13},
  year         = {2013},
}