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Alzrigat, M., Párraga, A. A., Agarwal, P., Zureigat, H., Österborg, A., Nahi, H., . . . Jernberg Wiklund, H. (2017). EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.. OncoTarget, 8(6), 10213-10224
Öppna denna publikation i ny flik eller fönster >>EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.
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2017 (Engelska)Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 6, s. 10213-10224Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite the fact that current treatment strategies have improved patients' median survival time, MM remains incurable. Epigenetic aberrations are emerging as important players in tumorigenesis making them attractive targets for therapy in cancer including MM. Recently, we suggested the polycomb repressive complex 2 (PRC2) as a common denominator of gene silencing in MM and presented the PRC2 enzymatic subunit enhancer of zeste homolog 2 (EZH2) as a potential therapeutic target in MM. Here we further dissect the anti-myeloma mechanisms mediated by EZH2 inhibition and show that pharmacological inhibition of EZH2 reduces the expression of MM-associated oncogenes; IRF-4, XBP-1, PRDM1/BLIMP-1 and c-MYC. We show that EZH2 inhibition reactivates the expression of microRNAs with tumor suppressor functions predicted to target MM-associated oncogenes; primarily miR-125a-3p and miR-320c. ChIP analysis reveals that miR-125a-3p and miR-320c are targets of EZH2 and H3K27me3 in MM cell lines and primary cells. Our results further highlight that polycomb-mediated silencing in MM includes microRNAs with tumor suppressor activity. This novel role strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.

Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-312396 (URN)10.18632/oncotarget.14378 (DOI)000394181800106 ()28052011 (PubMedID)
Tillgänglig från: 2017-01-09 Skapad: 2017-01-09 Senast uppdaterad: 2019-04-14Bibliografiskt granskad
Alzrigat, M., Párraga, A. A., Majumder, M., Ma, A., Jin, J., Nilsson, K., . . . Jernberg Wiklund, H. (2017). The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomain. OncoTarget, 8(61), 103731-103743
Öppna denna publikation i ny flik eller fönster >>The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomain
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2017 (Engelska)Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 61, s. 103731-103743Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Multiple myeloma (MM) is a tumor of plasmablasts/plasma cells (PCs) characterized by the expansion of malignant PCs with complex genetic aberrations in the bone marrow (BM). Recent reports, by us and others, have highlighted the polycomb group (PcG) proteins as potential targets for therapy in MM. The PcG protein BMI-1 of the polycomb repressive complex 1 (PRC1) has been reported to be overexpressed and to possess oncogenic functions in MM. Herein, we report on the anti-myeloma effects of the BMI-1 inhibitor PTC-209 and demonstrate that PTC-209 is a potent anti-myeloma agent in vitro using MM cell lines and primary MM cells. We show that PTC-209 reduces the viability of MM cells via induction of apoptosis and reveal that the anti-MM actions of PTC-209 are mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, leaving other PRC1 subunits such as CBX-7 and the catalytic subunit RING1B unaffected. Importantly, we demonstrate that PTC-209 exhibits synergistic and additive anti-myeloma activity when combined with other epigenetic inhibitors targeting EZH2 and BET bromodomains. Collectively, these data qualify BMI-1 as a candidate for targeted therapy in MM alone or in combinations with epigenetic inhibitors directed to PRC2/EZH2 or BET bromodomains.

Nyckelord
Multiple Myeloma, Epigenetics, Polycomb, BMI-1, PTC-209
Nationell ämneskategori
Cancer och onkologi
Forskningsämne
Medicinsk vetenskap; Molekylär medicin
Identifikatorer
urn:nbn:se:uu:diva-313562 (URN)10.18632/oncotarget.21909 (DOI)000419562500079 ()29262596 (PubMedID)
Forskningsfinansiär
CancerfondenVetenskapsrådet
Tillgänglig från: 2017-01-20 Skapad: 2017-01-20 Senast uppdaterad: 2019-04-14Bibliografiskt granskad
Agarwal, P., Kalushkova, A., Enroth, S., Alzrigat, M., Osterborg, A., Nilsson, K., . . . Jernberg-Wiklund, H. (2014). An Epigenomic Map of Multiple Myeloma Reveals the Importance of Polycomb Gene Silencing for the Malignancy. Blood, 124(21)
Öppna denna publikation i ny flik eller fönster >>An Epigenomic Map of Multiple Myeloma Reveals the Importance of Polycomb Gene Silencing for the Malignancy
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2014 (Engelska)Ingår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, nr 21Artikel i tidskrift, Meeting abstract (Övrigt vetenskapligt) Published
Nationell ämneskategori
Hematologi
Identifikatorer
urn:nbn:se:uu:diva-249065 (URN)000349242704040 ()
Tillgänglig från: 2015-04-20 Skapad: 2015-04-10 Senast uppdaterad: 2017-12-04Bibliografiskt granskad
Andersson, S., Nilsson, K., Fagerberg, L., Hallstrom, B. M., Sundström, C., Danielsson, A., . . . Asplund, A. (2014). The Transcriptomic and Proteomic Landscapes of Bone Marrow and Secondary Lymphoid Tissues. PLoS ONE, 9(12), e115911
Öppna denna publikation i ny flik eller fönster >>The Transcriptomic and Proteomic Landscapes of Bone Marrow and Secondary Lymphoid Tissues
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2014 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 12, s. e115911-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: The sequencing of the human genome has opened doors for global gene expression profiling, and the immense amount of data will lay an important ground for future studies of normal and diseased tissues. The Human Protein Atlas project aims to systematically map the human gene and protein expression landscape in a multitude of normal healthy tissues as well as cancers, enabling the characterization of both housekeeping genes and genes that display a tissue-specific expression pattern. This article focuses on identifying and describing genes with an elevated expression in four lymphohematopoietic tissue types (bone marrow, lymph node, spleen and appendix), based on the Human Protein Atlas-strategy that combines high throughput transcriptomics with affinity-based proteomics. Results: An enriched or enhanced expression in one or more of the lymphohematopoietic tissues, compared to other tissue-types, was seen for 693 out of 20,050 genes, and the highest levels of expression were found in bone marrow for neutrophilic and erythrocytic genes. A majority of these genes were found to constitute well-characterized genes with known functions in lymphatic or hematopoietic cells, while others are not previously studied, as exemplified by C19ORF59. Conclusions: In this paper we present a strategy of combining next generation RNA-sequencing with in situ affinity-based proteomics in order to identify and describe new gene targets for further research on lymphatic or hematopoietic cells and tissues. The results constitute lists of genes with enriched or enhanced expression in the four lymphohematopoietic tissues, exemplified also on protein level with immunohistochemical images.

Nationell ämneskategori
Övrig annan medicin och hälsovetenskap Klinisk laboratoriemedicin
Forskningsämne
Patologi
Identifikatorer
urn:nbn:se:uu:diva-243679 (URN)10.1371/journal.pone.0115911 (DOI)000347239900109 ()25541736 (PubMedID)
Forskningsfinansiär
Knut och Alice Wallenbergs Stiftelse, KAW2008.0143
Tillgänglig från: 2015-02-19 Skapad: 2015-02-11 Senast uppdaterad: 2019-04-02Bibliografiskt granskad
Myhrinder, A. L., Hellqvist, E., Bergh, A.-C., Jansson, M., Nilsson, K., Hultman, P., . . . Rosen, A. (2013). Molecular characterization of neoplastic and normal "sister" lymphoblastoid B-cell lines from chronic lymphocytic leukemia. Leukemia and Lymphoma, 54(8), 1769-1779
Öppna denna publikation i ny flik eller fönster >>Molecular characterization of neoplastic and normal "sister" lymphoblastoid B-cell lines from chronic lymphocytic leukemia
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2013 (Engelska)Ingår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 54, nr 8, s. 1769-1779Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Chronic lymphocytic leukemia (CLL) B-cells resemble self-renewing CD5 + B-cells carrying auto/xeno-antigen-reactive B-cell receptors (BCRs) and multiple innate pattern-recognition receptors, such as Toll-like receptors and scavenger receptors. Integration of signals from BCRs with multiple surface membrane receptors determines whether the cells will be proliferating, anergic or apoptotic. To better understand the role of antigen in leukemogenesis, CLL cell lines producing monoclonal antibodies (mAbs) will facilitate structural analysis of antigens and supply DNA for genetic studies. We present here a comprehensive genotypic and phenotypic characterization of available CLL and normal B-cell-derived lymphoblastoid cell lines (LCLs) from the same individuals (n = 17). Authenticity and verification studies of CLL-patient origin were done by IGHV sequencing, fluorescence in situ hybridization (FISH) and DNA/short tandem repeat (STR) fingerprinting. Innate B-cell features, i.e. natural Ab production and CD5 receptors, were present in most CLL cell lines, but in none of the normal LCLs. This panel of immortalized CLL-derived cell lines is a valuable reference representing a renewable source of authentic Abs and DNA.

Nyckelord
Chronic lymphocytic leukemia (CLL), lymphoblastoid cell line (LCL), IGHV sequence, cell-of-origin, natural antibodies, antigen structure, CD5+innate B-cells
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-206436 (URN)10.3109/10428194.2013.764418 (DOI)000321763800032 ()
Tillgänglig från: 2013-09-05 Skapad: 2013-08-30 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
Dimberg, L. Y., Dimberg, A., Ivarsson, K., Fryknäs, M., Rickardson, L., Tobin, G., . . . Wiklund, H. J. (2012). Stat1 activation attenuates IL-6 induced Stat3 activity but does not alter apoptosis sensitivity in multiple myeloma. BMC Cancer, 12, 318
Öppna denna publikation i ny flik eller fönster >>Stat1 activation attenuates IL-6 induced Stat3 activity but does not alter apoptosis sensitivity in multiple myeloma
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2012 (Engelska)Ingår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, s. 318-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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.

Nyckelord
Hematopoetic malignancies, Multiple myeloma, Apoptosis, IFN, Stat1, Stat3, Drug sensitivity
Nationell ämneskategori
Naturvetenskap
Identifikatorer
urn:nbn:se:uu:diva-187735 (URN)10.1186/1471-2407-12-318 (DOI)000310630800001 ()
Tillgänglig från: 2012-12-10 Skapad: 2012-12-10 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
Mohlin, S., Pietras, A., Wigerup, C., Ora, I., Andang, M., Nilsson, K., . . . Pahlman, S. (2012). Tumor-Initiating Cells in Childhood Neuroblastoma: Letter [Letter to the editor]. Cancer Research, 72(3), 821-822
Öppna denna publikation i ny flik eller fönster >>Tumor-Initiating Cells in Childhood Neuroblastoma: Letter
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2012 (Engelska)Ingår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 72, nr 3, s. 821-822Artikel i tidskrift, Letter (Refereegranskat) Published
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-170306 (URN)10.1158/0008-5472.CAN-11-1761 (DOI)000300405900026 ()
Tillgänglig från: 2012-03-12 Skapad: 2012-03-11 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
Kanduri, M., Tobin, G., Åleskog, A., Nilsson, K. & Rosenquist, R. (2011). The novel NF-kappa B inhibitor IMD-0354 induces apoptosis in chronic lymphocytic leukemia. Blood Cancer Journal, 1, e12
Öppna denna publikation i ny flik eller fönster >>The novel NF-kappa B inhibitor IMD-0354 induces apoptosis in chronic lymphocytic leukemia
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2011 (Engelska)Ingår i: Blood Cancer Journal, ISSN 2044-5385, E-ISSN 2044-5385, Vol. 1, s. e12-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Nuclear factor-kappa B (NF-kappa B) is an important regulator of cell survival and has been shown to be constitutively active in chronic lymphocytic leukemia (CLL) cells. Recently, a novel NF-kappa B inhibitor, IMD-0354 (N-(3, 5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide), was shown to specifically inhibit the phosphorylation of I kappa B alpha by IkB kinases, thus preventing NF-kappa B release. In this study, we investigated if IMD-0354 can inhibit NF-kappa B activation and induce apoptosis in CLL cells in vitro. The rate of increase in apoptosis, drug sensitivity and DNA-binding activity of NF-kappa B were studied using Annexin V stainings, the fluorometric microculture cytotoxicity assay and electrophoretic mobility shift assay, respectively. Finally, the impact of IMD-0354 treatment on the expression of a set of apoptosis-related genes was investigated. The results clearly show that IMD-0354 induced apoptosis (mean 26%, range 8-48%) in CLL cells, independent of immunoglobulin heavy variable (IGHV) gene mutational status, and showed a dose-dependent cytotoxic effect. IMD-0354 treatment also significantly lowered the DNA-binding activity of NF-kappa B in CLL cells. In addition, we identified differences in expression levels of pro- and antiapoptotic genes following IMD-0354 treatment. In summary, our novel findings show that IMD-0354 can induce apoptosis in CLL cells, and thus merits further investigation as an anticancer agent in vivo.

Nyckelord
chronic lymphocytic leukemia, IMD-0354, nuclear factor-kappa B, apoptosis, drug sensitivity
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-168436 (URN)10.1038/bcj.2011.9 (DOI)000298815400006 ()
Tillgänglig från: 2012-02-10 Skapad: 2012-02-10 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
Kalushkova, A., Fryknäs, M., Lemaire, M., Fristedt, C., Agarwal, P., Eriksson, M., . . . Jernberg-Wiklund, H. (2010). Polycomb target genes are silenced in multiple myeloma. PLoS ONE, 5(7), e11483
Öppna denna publikation i ny flik eller fönster >>Polycomb target genes are silenced in multiple myeloma
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2010 (Engelska)Ingår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, nr 7, s. e11483-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Multiple myeloma (MM) is a genetically heterogeneous disease, which to date remains fatal. Finding a common mechanism for initiation and progression of MM continues to be challenging. By means of integrative genomics, we identified an underexpressed gene signature in MM patient cells compared to normal counterpart plasma cells. This profile was enriched for previously defined H3K27-tri-methylated genes, targets of the Polycomb group (PcG) proteins in human embryonic fibroblasts. Additionally, the silenced gene signature was more pronounced in ISS stage III MM compared to stage I and II. Using chromatin immunoprecipitation (ChIP) assay on purified CD138+ cells from four MM patients and on two MM cell lines, we found enrichment of H3K27me3 at genes selected from the profile. As the data implied that the Polycomb-targeted gene profile would be highly relevant for pharmacological treatment of MM, we used two compounds to chemically revert the H3K27-tri-methylation mediated gene silencing. The S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin (DZNep) and the histone deacetylase inhibitor LBH589 (Panobinostat), reactivated the expression of genes repressed by H3K27me3, depleted cells from the PRC2 component EZH2 and induced apoptosis in human MM cell lines. In the immunocompetent 5T33MM in vivo model for MM, treatment with LBH589 resulted in gene upregulation, reduced tumor load and increased overall survival. Taken together, our results reveal a common gene signature in MM, mediated by gene silencing via the Polycomb repressor complex. The importance of the underexpressed gene profile in MM tumor initiation and progression should be subjected to further studies.

Nationell ämneskategori
Hematologi
Identifikatorer
urn:nbn:se:uu:diva-133207 (URN)10.1371/journal.pone.0011483 (DOI)000279715300003 ()20634887 (PubMedID)
Tillgänglig från: 2010-11-03 Skapad: 2010-11-03 Senast uppdaterad: 2017-12-12Bibliografiskt granskad
Tshuikina, M., Jernberg-Wiklund, H., Nilsson, K. & Öberg, F. (2008). Epigenetic silencing of the interferon regulatory factor ICSBP/IRF8 in human multiple myeloma. Experimental Hematology, 36(12), 1673-1681
Öppna denna publikation i ny flik eller fönster >>Epigenetic silencing of the interferon regulatory factor ICSBP/IRF8 in human multiple myeloma
2008 (Engelska)Ingår i: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 36, nr 12, s. 1673-1681Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

OBJECTIVE: Multiple myeloma (MM) is presently an incurable malignant plasma cell tumor. The objective of this study was to investigate expression of the interferon regulatory factor family (IRF1-9) and the potential role of DNA methylation in silencing IRF genes in MM cell lines and purified MM cells from patients. MATERIALS AND METHODS: Using a panel of 13 human MM cell lines and purified CD138+ cells from nine MM patients, expression of IRF genes was investigated by quantitative reverse transcriptase polymerase chain reaction and Western blot. DNA methylation of the interferon consensus sequence-binding protein (ICSBP/IRF8) gene was measured using pyrosequencing, and the effect of promoter methylation on expression was analyzed by in vitro methylation of a cloned ICSBP/IRF8 promoter, and treatment of MM cells with 5-aza-2'-deoxycytidine (DAC). RESULTS: Eight of thirteen of the MM cell lines were found to lack ICSBP/IRF8 expression, associated with hypermethylation of the CpG island in the ICSBP/IRF8 promoter. We also found that ICSBP/IRF8 was significantly underexpressed in primary MM cells, whereas the ICSBP/IRF8 promoter was methylated in only one of nine of primary purified CD138+ MM samples. DAC-mediated demethylation restored endogenous ICSBP/IRF8 expression, whereas in vitro methylation silenced the promoter. CONCLUSION: Expression of the ICSBP/IRF8 gene is silenced in a majority of MM cell lines and primary CD138+ MM cells. DNA methylation of the ICSBP/IRF8 gene is a frequent event in MM cell lines, but silencing is also observed in the absence of methylation. These results suggest that silencing of ICSBP/IRF8 expression, by DNA methylation or other epigenetic mechanisms, may be associated with the malignant phenotype of MM.

Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-87845 (URN)10.1016/j.exphem.2008.08.001 (DOI)000261370000011 ()18922617 (PubMedID)
Tillgänglig från: 2009-01-14 Skapad: 2009-01-14 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
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