| 1. |
- 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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| 2. |
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| 3. |
- Kalliara, Eirini, et al.
(författare)
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Spatially Guided and Single Cell Tools to Map the Microenvironment in Cutaneous T-Cell Lymphoma
- 2023
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Ingår i: Cancers. - 2072-6694. ; 15:8, s. 1-15
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Tidskriftsartikel (refereegranskat)abstract
- Mycosis fungoides (MF) and Sézary syndrome (SS) are two closely related clinical variants of cutaneous T-cell lymphomas (CTCL). Previously demonstrated large patient-to-patient and intra-patient disease heterogeneity underpins the importance of personalized medicine in CTCL. Advanced stages of CTCL are characterized by dismal prognosis, and the early identification of patients who will progress remains a clinical unmet need. While the exact molecular events underlying disease progression are poorly resolved, the tumor microenvironment (TME) has emerged as an important driver. In particular, the Th1-to-Th2 shift in the immune response is now commonly identified across advanced-stage CTCL patients. Herein, we summarize the role of the TME in CTCL evolution and the latest studies in deciphering inter- and intra-patient heterogeneity. We introduce spatially resolved omics as a promising technology to advance immune-oncology efforts in CTCL. We propose the combined implementation of spatially guided and single-cell omics technologies in paired skin and blood samples. Such an approach will mediate in-depth profiling of phenotypic and molecular changes in reactive immune subpopulations and malignant T cells preceding the Th1-to-Th2 shift and reveal mechanisms underlying disease progression from skin-limited to systemic disease that collectively will lead to the discovery of novel biomarkers to improve patient prognostication and the design of personalized treatment strategies.
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| 4. |
- Kofoed Damm, Jesper, et al.
(författare)
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Pharmacologically relevant doses of valproate upregulate CD20 expression in three diffuse large B-cell lymphoma patients in vivo.
- 2015
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Ingår i: Experimental hematology & oncology. - : Springer Science and Business Media LLC. - 2162-3619. ; 4:4
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetic code modifications by histone deacetylase inhibitors (HDACi) have been proposed as potential new therapies for lymphoid malignancies. Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive lymphoma for which standard first line treatment is the chemotherapy regimen CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) combined with the monoclonal anti-CD20 antibody rituximab (R-CHOP). The HDACi valproate, which has for long been utilized in anti-convulsive therapy, has been shown to sensitize to chemotherapy in vitro. Valproate upregulates expression of CD20 in lymphoma cell lines; therefore, 48 hour pre-treatment with valproate before first line R-CHOP in DLBCL stages II-IV is evaluated in the phase I clinical trial VALFRID; Valproate as First line therapy in combination with Rituximab and CHOP in Diffuse large B-cell lymphoma.
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| 5. |
- Montano, Giorgia, et al.
(författare)
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The hematopoietic tumor suppressor interferon regulatory factor 8 (IRF8) is upregulated by the antimetabolite cytarabine in leukemic cells involving the zinc finger protein ZNF224, acting as a cofactor of the Wilms' tumor gene 1 (WT1) protein.
- 2016
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Ingår i: Leukemia Research: A Forum for Studies on Leukemia and Normal Hemopoiesis. - : Elsevier BV. - 1873-5835. ; 40:1, s. 60-67
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Tidskriftsartikel (refereegranskat)abstract
- The transcription factor interferon regulatory factor-8 (IRF8) is highly expressed in myeloid progenitors, while most myeloid leukemias show low or absent expression. Loss of IRF8 in mice leads to a myeloproliferative disorder, indicating a tumor-suppressive role of IRF8. The Wilms tumor gene 1 (WT1) protein represses the IRF8-promoter. The zinc finger protein ZNF224 can act as a transcriptional co-factor of WT1 and potentiate the cytotoxic response to the cytostatic drug cytarabine. We hypothesized that cytarabine upregulates IRF8 and that transcriptional control of IRF8 involves WT1 and ZNF224. Treatment of leukemic K562 cells with cytarabine upregulated IRF8 protein and mRNA, which was correlated to increased expression of ZNF224. Knock down of ZNF224 with shRNA suppressed both basal and cytarabine-induced IRF8 expression. While ZNF224 alone did not affect IRF8 promoter activity, ZNF224 partially reversed the suppressive effect of WT1 on the IRF8 promoter, as judged by luciferase reporter experiments. Coprecipitation revealed nuclear binding of WT1 and ZNF224, and by chromatin immunoprecipitation (ChIP) experiments it was demonstrated that WT1 recruits ZNF224 to the IRF8 promoter. We conclude that cytarabine-induced upregulation of the IRF8 in leukemic cells involves increased levels of ZNF224, which can counteract the repressive activity of WT1 on the IRF8-promoter.
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| 6. |
- Nilsson, Helena Jernmark, et al.
(författare)
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The transcriptional coregulator NAB2 is a target gene for the Wilms' tumor gene 1 protein (WT1) in leukemic cells
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:50, s. 87136-87150
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Tidskriftsartikel (refereegranskat)abstract
- The Wilms' tumor gene 1 (WT1) is recurrently mutated in acute myeloid leukemia. Mutations and high expression of WT1 associate with a poor prognosis. In mice, WT1 cooperates with the RUNX1/RUNX1T1 (AML1/ETO) fusion gene in the induction of acute leukemia, further emphasizing a role for WT1 in leukemia development. Molecular mechanisms for WT1 are, however, incompletely understood. Here, we identify the transcriptional coregulator NAB2 as a target gene of WT1. Analysis of gene expression profiles of leukemic samples revealed a positive correlation between the expression of WT1 and NAB2, as well as a non-zero partial correlation. Overexpression of WT1 in hematopoietic cells resulted in increased NAB2 levels, while suppression of WT1 decreased NAB2 expression. WT1 bound and transactivated the proximal NAB2 promoter, as shown by ChIP and reporter experiments, respectively. ChIP experiments also revealed that WT1 can recruit NAB2 to the IRF8 promoter, thus modulating the transcriptional activity of WT1, as shown by reporter experiments. Our results implicate NAB2 as a previously unreported target gene of WT1 and that NAB2 acts as a transcriptional cofactor of WT1.
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| 7. |
- Obad, Susanna, et al.
(författare)
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Expression of the IFN-inducible p53-target gene TRIM22 is down-regulated during erythroid differentiation of human bone marrow.
- 2007
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Ingår i: Leukemia Research: A Forum for Studies on Leukemia and Normal Hemopoiesis. - : Elsevier BV. - 1873-5835. ; 31:7, s. 995-1001
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Tidskriftsartikel (refereegranskat)abstract
- The interferon inducible protein TRIM22 has been identified as a p53 target gene, with possible involvement in proliferation and differentiation of leukaemia cells. Here, the expression levels of TRIM22 during haematopoietic differentiation are characterised. Expression of TRIM22 correlates inversely to differentiation, as TRIM22 is highly expressed in CD34(+) human bone marrow progenitor cells, but declines in mature populations. The erythroid lineage appears as a special case, as TRIM22 expression shows an extreme decrease during late erythroid maturation and is completely undetectable in nucleated erythroid populations in contrast to other lineages. In conclusion, our data Could suggest lineage-specific roles for TRIM22 during haematopoietic differentiation.
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| 8. |
- Obad, Susanna, et al.
(författare)
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Regulation of the interferon-inducible p53 target gene TRIM22 (Staf50) in human T lymphocyte activation
- 2007
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Ingår i: Journal of Interferon and Cytokine Research. - : Mary Ann Liebert Inc. - 1079-9907 .- 1557-7465. ; 27:10, s. 857-864
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Tidskriftsartikel (refereegranskat)abstract
- TRIM22 (Staf50) is an interferon (IFN)-inducible protein with unknown function. Recently, we identified TRIM22 as a novel p53 target gene and showed that overexpression of TRIM22 inhibits the clonogenic growth of monoblastic U937 cells. Moreover, expression of TRIM22 is high in lymphoid tissue, and levels decrease during T lymphocyte activation with CD3/CD2/CD28, suggesting that TRIM22 could exert antiproliferative effects. Here, a prominent increase in TRIM22 levels is observed during activation with interleukin-2 (IL-2) or IL-15 in contrast to the decrease observed during CD3/CD2/CD28-induced activation. However, stimulation of cells in these experiments was performed on crude T lymphocytes, allowing indirect regulation between different lymphocyte subtypes to take place. Therefore, to prevent interaction between different lymphocyte subtypes, expression of TRIM22 was examined during activation of sorted T lymphocyte subpopulations. In contrast to the marked changes of TRIM22 during activation of crude T lymphocytes, in isolated subpopulations, TRIM22 expression was not significantly affected in spite of IL-2-induced or CD3/CD2/CD28-induced activation. In addition, in contrast to the TRIM22 mouse ortholog Rpt-1, TRIM22 did not affect levels of CD25 (IL-2R alpha) mRNA. Our data suggest a more complex role for TRIM22 during T lymphocyte activation than merely as an antiproliferative factor. TRIM22 probably has an activation stage-specific role connected to the paracrine crosstalk during T lymphocyte activation.
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| 9. |
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| 10. |
- Petersson, Jessica, et al.
(författare)
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The human IFN-inducible p53 target gene TRIM22 colocalizes with the centrosome independently of cell cycle phase.
- 2010
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 316, s. 568-579
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Tidskriftsartikel (refereegranskat)abstract
- TRIM22 (Staf50), a member of the TRIM protein family, is an interferon (IFN)-inducible protein as well as a p53 target gene. The function of TRIM22 is largely unknown, but TRIM22 is suggested to play a role in viral defense by restriction of viral replication. In addition, TRIM22 may function as a ubiquitin E3 ligase. In contrast to previous reports showing solely cytoplasmic localization of exogenous TRIM22, we report here that endogenous TRIM22 is localized to both nucleus and cytosol in primary human mononuclear cells, as well as in the human osteosarcoma cell line U2OS. Moreover, we demonstrate a colocalization of TRIM22 with the centrosomes in primary cells as well as in U2OS cells, and show that this colocalization is independent of cell cycle phase. Additionally, our data suggest the colocalization with centrosomes to be independent on the microtubule network. Given that some viral protein assembly takes place in the close vicinity of the centrosome, our data suggest that important functions of TRIM22 such as regulation of viral replication and protein degradation may take place in the centrosome. However, further studies are warranted to certify this notion.
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