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Sökning: WFRF:(Gullberg Urban)

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1.
  • Ali, Mina, et al. (författare)
  • The multiple myeloma risk allele at 5q15 lowers ELL2 expression and increases ribosomal gene expression
  • 2018
  • Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Recently, we identified ELL2 as a susceptibility gene for multiple myeloma (MM). To understand its mechanism of action, we performed expression quantitative trait locus analysis in CD138+ plasma cells from 1630 MM patients from four populations. We show that the MM risk allele lowers ELL2 expression in these cells (P combined = 2.5 × 10-27; β combined = -0.24 SD), but not in peripheral blood or other tissues. Consistent with this, several variants representing the MM risk allele map to regulatory genomic regions, and three yield reduced transcriptional activity in plasmocytoma cell lines. One of these (rs3777189-C) co-locates with the best-supported lead variants for ELL2 expression and MM risk, and reduces binding of MAFF/G/K family transcription factors. Moreover, further analysis reveals that the MM risk allele associates with upregulation of gene sets related to ribosome biogenesis, and knockout/knockdown and rescue experiments in plasmocytoma cell lines support a cause-effect relationship. Our results provide mechanistic insight into MM predisposition.
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2.
  • Dimberg, Lina Y., et al. (författare)
  • Stat1 activation attenuates IL-6 induced Stat3 activity but does not alter apoptosis sensitivity in multiple myeloma
  • 2012
  • Ingår i: BMC Cancer. - : BioMed Central (BMC). - 1471-2407 .- 1471-2407. ; 12, s. 318-
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Multiple myeloma (MM) is at present an incurable malignancy, characterized by apoptosis-resistant tumor cells. Interferon (IFN) treatment sensitizes MM cells to Fas-induced apoptosis and is associated with an increased activation of Signal transducer and activator of transcription (Stat)1. The role of Stat1 in MM has not been elucidated, but Stat1 has in several studies been ascribed a pro-apoptotic role. Conversely, IL-6 induction of Stat3 is known to confer resistance to apoptosis in MM. Methods: To delineate the role of Stat1 in IFN mediated sensitization to apoptosis, sub-lines of the U-266-1970 MM cell line with a stable expression of the active mutant Stat1C were utilized. The influence of Stat1C constitutive transcriptional activation on endogenous Stat3 expression and activation, and the expression of apoptosis-related genes were analyzed. To determine whether Stat1 alone would be an important determinant in sensitizing MM cells to apoptosis, the U-266-1970-Stat1C cell line and control cells were exposed to high throughput compound screening (HTS). Results: To explore the role of Stat1 in IFN mediated apoptosis sensitization of MM, we established sublines of the MM cell line U-266-1970 constitutively expressing the active mutant Stat1C. We found that constitutive nuclear localization and transcriptional activity of Stat1 was associated with an attenuation of IL-6-induced Stat3 activation and up-regulation of mRNA for the pro-apoptotic Bcl-2 protein family genes Harakiri, the short form of Mcl-1 and Noxa. However, Stat1 activation alone was not sufficient to sensitize cells to Fas-induced apoptosis. In a screening of > 3000 compounds including bortezomib, dexamethasone, etoposide, suberoylanilide hydroxamic acid (SAHA), geldanamycin (17-AAG), doxorubicin and thalidomide, we found that the drug response and IC50 in cells constitutively expressing active Stat1 was mainly unaltered. Conclusion: We conclude that Stat1 alters IL-6 induced Stat3 activity and the expression of pro-apoptotic genes. However, this shift alone is not sufficient to alter apoptosis sensitivity in MM cells, suggesting that Stat1 independent pathways are operative in IFN mediated apoptosis sensitization.
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5.
  • Hakansson, P., et al. (författare)
  • Establishment and phenotypic characterization of human U937 cells with inducible P210 BCR/ABL expression reveals upregulation of CEACAM1 (CD66a)
  • 2004
  • Ingår i: Leukemia. - : Nature Publishing Group. - 0887-6924 .- 1476-5551. ; 18:3, s. 538-47
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic myeloid leukemia (CML) is characterized by the expression of the P210 BCR/ABL fusion protein. The molecular mechanisms behind this oncogene-mediated hematological disease are, however, not fully understood. Here, we describe the establishment and phenotypic characterization of U937 cells in which P210 BCR/ABL can be conditionally expressed using tetracycline. The induction of BCR/ABL in the obtained clones resulted in a rapid phosphorylation of the STAT1, STAT3 and STAT5 molecules, consistent with the findings in other model systems. Phenotypic characterization of the clones revealed that BCR/ABL induces a slight decrease in the proliferation and viability, without a marked effect on cell cycle distribution, the rate of apoptosis or on cellular differentiation, as judged by several cell surface markers and capacity to reduce nitro blue tetrazolium. Interestingly, BCR/ABL was found to upregulate the expression of carcinoembryonic-related antigen (CEA)CAM1 (CD66a), which is a plasma membrane-linked glycoprotein belonging to the CEAs and involved in signal transduction and cellular adhesion. The expression of CEACAM1 was reversible upon imatinib treatment in BCR/ABL-expressing U937 cells as well as in BCR/ABL-positive K562 cells. The established cell lines may prove useful in further modeling and dissection of BCR/ABL-induced leukemogenesis.
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7.
  • Mitchell, Jonathan S., et al. (författare)
  • Genome-wide association study identifies multiple susceptibility loci for multiple myeloma
  • 2016
  • Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723 .- 2041-1723. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P = 1.31 x 10(-8)), 6q21 (rs9372120, P = 9.09 x 10(-15)), 7q36.1 (rs7781265, P = 9.71 x 10(-9)), 8q24.21 (rs1948915, P = 4.20 x 10(-11)), 9p21.3 (rs2811710, P = 1.72 x 10(-13)), 10p12.1 (rs2790457, P = 1.77 x 10(-8)), 16q23.1 (rs7193541, P = 5.00 x 10(-12)) and 20q13.13 (rs6066835, P = 1.36 x 10(-13)), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.
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8.
  • Nilsson, Helena Jernmark, et al. (författare)
  • The transcriptional coregulator NAB2 is a target gene for the Wilms' tumor gene 1 protein (WT1) in leukemic cells
  • 2017
  • Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:50, s. 87136-87150
  • 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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9.
  • Sandén, Carl, et al. (författare)
  • Forced expression of the DEK-NUP214 fusion protein promotes proliferation dependent on upregulation of mTOR
  • 2013
  • Ingår i: BMC Cancer. - : BioMed Central (BMC). - 1471-2407. ; 13
  • 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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