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| 2. |
- Ageberg, Malin, et al.
(författare)
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Identification of a novel and myeloid specific role of the leukemia-associated fusion protein DEK-NUP214 leading to increased protein synthesis.
- 2008
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 47, s. 276-287
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Tidskriftsartikel (refereegranskat)abstract
- The t(6;9)(p22;q34) chromosomal translocation is found in a subset of patients with acute myeloid leukemia (AML). The translocation results in a fusion between the nuclear phosphoprotein DEK and the nucleoporin NUP214 (previously CAN). The mechanism by which the fusion protein DEK-NUP214 contributes to leukemia development has not been identified, and disruptions of normal cellular functions by DEK-NUP214 have previously not been described. In the present study, a novel effect of the DEK-NUP214 fusion protein is demonstrated. Our findings reveal a substantial increase in global protein synthesis in DEK-NUP214 expressing cells. Furthermore, we conclude that this effect is not the result of dysregulated transcription but merely due to increased translation. Consistent with the association with AML, the increased protein synthesis mediated by DEK-NUP214 is restricted to cells of the myeloid lineage. Analysis of potential mechanisms for regulating protein synthesis shows that expression of DEK-NUP214 correlates to the phosphorylation of the translation initiation protein, EIF4E. The present data provide evidence that increase of translational activity constitutes a mechanism by which the leukemogenic effect of DEK-NUP124 may be mediated. (c) 2008 Wiley-Liss, Inc.
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| 3. |
- Ageberg, Malin, et al.
(författare)
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Inhibition of geranylgeranylation mediates sensitivity to CHOP-induced cell death of DLBCL cell lines.
- 2011
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 317, s. 1179-1191
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Tidskriftsartikel (refereegranskat)abstract
- Prenylation is a post-translational hydrophobic modification of proteins, important for their membrane localization and biological function. The use of inhibitors of prenylation has proven to be a useful tool in the activation of apoptotic pathways in tumor cell lines. Rab geranylgeranyl transferase (Rab GGT) is responsible for the prenylation of the Rab family. Overexpression of Rab GGTbeta has been identified in CHOP refractory diffuse large B cell lymphoma (DLBCL). Using a cell line- based model for CHOP resistant DLBCL, we show that treatment with simvastatin, which inhibits protein farnesylation and geranylgeranylation, sensitises DLBCL cells to cytotoxic treatment. Treatment with the farnesyl transferase inhibitor, FTI-277, or the geranylgeranyl transferase I inhibitor, GGTI-298, indicates that the reduction in cell viability was restricted to inhibition of geranylgeranylation. In addition, treatment with BMS1, a combined inhibitor of farnesyl transferase and Rab GGT, resulted in a high cytostatic effect in WSU-NHL cells, demonstrated by reduced cell viability and decreased proliferation. Co-treatment of BMS1 or GGTI-298 with CHOP showed synergistic effects with regard to markers of apoptosis. We propose that inhibition of protein geranylgeranylation together with conventional cytostatic therapy is a potential novel strategy for treating patients with CHOP refractory DLBCL.
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| 4. |
- Ageberg, Malin
(författare)
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On the role of the fusion protein DEK-NUP214 in leukemogenesis
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The t(6;9) translocation is found in a subset of patients with acute myeloid leukemia (AML) and is associated with a poor prognosis. The translocation results in the formation of the DEK-NUP214 fusion protein containing almost the entire nuclear protein DEK and two thirds of the nucleoporin NUP214. The molecular mechanisms behind the leukemic conversion of cells expressing the fusion protein DEK-NUP214 have not yet been elucidated. We have identified that cells expressing DEK-NUP214 show increased protein synthesis and proproliferative effects of DEK and DEK-NUP214 have been discovered. In addition, the effect of DEK-NUP214 is independent of transcriptional activity or transactivational capacity. By bioinformatics analysis, using a publicly available dataset of patients with AML, we could also confirm the altered translational control in those patients carrying the t(6;9) translocation. By sequence analysis of DEK-NUP214, a consensus-binding motif for the eukaryotic initiation factor 4E (eIF?E) was revealed. The eIF4E protein is considered the most important factor during translational initiation as well as being crucial for nucleocytoplasmic export of specific transcript important for cell proliferation, differentiation and apoptosis. We have identified a direct interaction between DEK-NUP214 and eIF4E, indicating a link between the functions of eIF4E and the dysregulated mRNA translation caused by DEK-NUP214. Furthermore, we suggest that the increased protein synthesis caused by DEK-NUP214 is the result of dysregulated nucleocytoplasmic functions of eIF4E based on interaction studies, overexpression of the negative regulator of eIF4E, the proline-rich homeodomain protein (PRH), and treatment with leptomycin B. Moreover, we have also discovered a myeloid specificity of the effect on protein synthesis caused by DEK-NUP214, concordant with the tissue-specific expression pattern of PRH, suggesting a cell context specific regulation of the functions of eIF4E. In conclusion, we have revealed the first dysregulated cellular mechanism caused by the leukemia-associated fusion protein DEK-NUP214 in myeloid cells. Altered mRNA translation is strongly implicated in tumorigenesis and is likely to be involved in the malignant transformation of DEK-NUP214 expressing cells. The increasing availability of substances interfering with translational regulation could lead to altered and improved therapy of AML patient with the t(6;9) translocation.
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| 5. |
- Ageberg, Malin, et al.
(författare)
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The histone deacetylase inhibitor valproic acid sensitizes diffuse large B-cell lymphoma cell lines to CHOP-induced cell death.
- 2013
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Ingår i: American Journal of Translational Research. - 1943-8141. ; 5:2, s. 170-183
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetic code modifications by histone deacetylase inhibitors (HDACis) have recently been proposed as potential new therapies for hematological malignancies. Diffuse large B-cell lymphoma (DLBCL) is the most common form of aggressive lymphoma. At present, standard first line treatment for DLBCL patients is the antracycline-based chemotherapy regimen CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) combined with the monoclonal anti-CD20 antibody rituximab (R-CHOP). Since only 50-60% of patients reach a long-time cure by this treatment, there is an urgent need for novel treatment strategies to increase the response and long-term remission to initial R-CHOP therapy. In this study, we investigated the effect of the HDAC inhibitor valproic acid (VPA) on DLBCL cell lines. To elucidate the effects of VPA on chemo-sensitivity, we used a cell-line based model of CHOP-refractory DLBCL. All five DLBCL cell lines treated with VPA alone or in combination with CHOP showed decreased viability and proliferation. The VPA-induced sensitization of DLBCL cells to cytotoxic treatment resulted in increased number of apoptotic cell as judged by annexin V-positivity and the presence of cleaved caspase-3. In addition, pretreatment with VPA resulted in a significantly increased DNA-damage as compared to CHOP alone. In summary, HDAC inhibitors such as VPA, are promising therapeutic agents in combination with R-CHOP for patients with DLBCL.
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| 6. |
- Ageberg, Malin, et al.
(författare)
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The involvement of cellular proliferation status in the expression of the human proto-oncogene DEK
- 2006
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Ingår i: Haematologica. - 1592-8721. ; 91:2, s. 268-269
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The role of the DEK protein, involved in the leukemia-associated fusion protein DEK-CAN, is not yet known. In this study, we show a higher expression of DEK mRNA in immature cells than in mature cells. Furthermore, a correlation between DEK expression and cell proliferation was demonstrated, suggesting that DEK plays a role in the proliferation of hematopoietic cells and raising the question of whether the DEK-CAN fusion protein might perturb regulation of proliferation in leukemic cells.
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| 7. |
- Sandén, Carl, et al.
(författare)
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Forced expression of the DEK-NUP214 fusion protein promotes proliferation dependent on upregulation of mTOR
- 2013
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 13
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Tidskriftsartikel (refereegranskat)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.
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