| 1. |
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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, 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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| 5. |
- Alzrigat, Mohammad
(författare)
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Targeted Inhibition of Polycomb Repressive Complexes in Multiple Myeloma : Implications for Biology and Therapy
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Multiple myeloma (MM) is a hematological malignancy of antibody producing plasmablasts/plasma cells. MM is characterized by extensive genetic and clonal heterogeneity, which have hampered the attempts to identify a common underlying mechanism for disease establishment and development of appropriate treatment regimes. This thesis is focused on understanding the role of epigenetic regulation of gene expression mediated by the polycomb repressive complexes 1 and 2 (PRC1 and 2) in MM and their impact on disease biology and therapy.In paper I the genome-wide distribution of two histone methylation marks; H3K27me3 and H3K4me3 were studied in plasma cells isolated from newly diagnosed MM patients or age-matched normal donors. We were able to define targets of H3K27me3, H3K4me3 and bivalent (carry both marks) which are, when compared to normal individuals, unique to MM patients. The presence of H3K27me3 correlated with silencing of MM unique H3K27me3 targets in MM patients at advanced stages of the disease. Notably, the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also showed that inhibition of the PRC2 enzymatic subunit EZH2 using highly selective inhibitors (GSK343 and UNC1999) demonstrated anti-myeloma activity using relevant in vitro models of MM. These data suggest an important role for gene repression mediated by PRC2 in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.In paper II we further explored the therapeutic potential of UNC1999, a highly selective inhibitor of EZH2 in MM. We showed that EZH2 inhibition by UNC1999 downregulated important MM oncogenes; IRF-4, XBP-1, BLIMP-1and c-MYC. These oncogenes have been previously shown to be crucial for disease establishment, growth and progression. We found that EZH2 inhibition reactivated the expression of microRNAs genes previously found to be underexpressed in MM and which possess potential tumor suppressor functions. Among the reactivated microRNAs we identified miR-125a-3p and miR-320c as predicted negative regulators of the MM-associated oncogenes. Notably, we defined miR-125a-3p and miR-320c as targets of EZH2 and H3K27me3 in MM cell lines and patients samples. These findings described for the first time PRC2/EZH2/H3K27me3 as regulators of microRNA with tumor suppressor functions in MM. This further strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.In paper III we evaluated the therapeutic potential of targeting PRC1 in MM using the recently developed chemical PTC-209; an inhibitor targeting the BMI-1 subunit of PRC1. Using MM cell lines and primary cells isolated from newly diagnosed or relapsed MM patients, we found that PTC-209 has a potent anti-MM activity. We showed, for the first time in MM, that PTC-209 anti-MM effects were mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, but that other subunits of the PRC1 complex were not affected. We showed that PTC-209 reduced MM cell viability via significant induction of apoptosis. More importantly, we demonstrated that PTC-209 shows synergistic anti-MM activity with other epigenetic inhibitors targeting EZH2 (UNC1999) and BET-bromodomains (JQ1). This work highlights the potential use of BMI-1 and PRC1 as potential therapeutic targets in MM alone or in combination with other anti-MM agents including epigenetic inhibitors.
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| 6. |
- Belfrage, Emma, et al.
(författare)
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Predictive and Prognostic Biomarkers in Patients With Mycosis Fungoides and Sézary Syndrome (BIO-MUSE) : Protocol for a Translational Study
- 2024
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Ingår i: JMIR Research Protocols. - 1929-0748. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Cutaneous T-cell lymphoma (CTCL) is a rare group of lymphomas that primarily affects the skin. Mycosis fungoides (MF) is the most common form of CTCL and Sézary syndrome (SS) is more infrequent. Early stages (IA-IIA) have a favorable prognosis, while advanced stages (IIB-IVB) have a worse prognosis. Around 25% of patients with early stages of the disease will progress to advanced stages. Malignant skin-infiltrating T-cells in CTCL are accompanied by infiltrates of nonmalignant T-cells and other immune cells that produce cytokines that modulate the inflammation. Skin infection, often with Staphylococcus aureus, is frequent in advanced stages and can lead to sepsis and death. S. aureus has also been reported to contribute to the progression of the disease. Previous reports indicate a shift from Th1 to Th2 cytokine production and dysfunction of the skin barrier in CTCL. Treatment response is highly variable and often unpredictable, and there is a need for new predictive and prognostic biomarkers.OBJECTIVE: This prospective translational study aims to identify prognostic biomarkers in the blood and skin of patients with MF and SS.METHODS: The Predictive and Prognostic Biomarkers in Patients With MF and SS (BIO-MUSE) study aims to recruit 120 adult patients with MF or SS and a control group of 20 healthy volunteers. The treatments will be given according to clinical routine. The sampling of each patient will be performed every 3 months for 3 years. The blood samples will be analyzed for lactate dehydrogenase, immunoglobulin E, interleukins, thymus and activation-regulated chemokine, and lymphocyte subpopulations. The lymphoma microenvironment will be investigated through digital spatial profiling and single-cell RNA sequencing. Microbiological sampling and analysis of skin barrier function will be performed. The life quality parameters will be evaluated. The results will be evaluated by the stage of the disease.RESULTS: Patient inclusion started in 2021 and is still ongoing in 2023, with 18 patients and 20 healthy controls enrolled. The publication of selected translational findings before the publication of the main results of the trial is accepted.CONCLUSIONS: This study aims to investigate blood and skin with a focus on immune cells and the microbiological environment to identify potential new prognostic biomarkers in MF and SS.TRIAL REGISTRATION: ClinicalTrials.gov NCT04904146; https://www.clinicaltrials.gov/study/NCT04904146.INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/55723.
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| 7. |
- Drott, Kristina
(författare)
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How can p53 induce differentiation of leukemic cells?
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The terminal differentiation of leukemic cells is closely connected to their death. The concept of differentiation therapy originates from the idea that forced maturation of leukemic cells could induce cell death without the side-effects that are provoked by ordinary chemotherapy. The tumour suppressor protein p53 is a transcription factor, and can induce cell cycle arrest and apoptosis of malignant cells. Importantly, p53 is also known to induce differentiation in many different tissues including leukemic cells. Thus, to restore p53-dependent pathways for differentiation is an attractive approach in the development of a functional differentiation therapy. However, further knowledge is necessary in order to realise such a concept. Therefore, the aim of this thesis was to better understand the pathways for p53-mediated differentiation of leukemic cells. To that end, a temperature inducible p53 mutant (ptsp53) was overexpressed in erythroleukemic K562 cells and monoblastic U-937-4 cells. We show that induced expression of p53 facilitates erythroid but not megakaryocytoid differentiation. Moreover, p53 can induce differentiation of U-937-4 cells in spite of inhibition of p53-mediated apoptosis as mediated by bcl-2. Also, the amount of active p53 seems to determine whether p53 will induce apoptosis or differentiation. In addition, p53-mediated differentiation depends on the transcription regulatory capacity of p53, but the p53 target gene p21 does not seem to be the key molecule mediating p53-induced differentiation. The Wilms tumour protein WT1 binds to p53, modulating its functions. Our data demonstrate that WT1 interferes with the differentiation of monoblastic U-937-4 cells, suggesting that WT1 could have a role in the differentiation block of acute leukemia. In conclusion, our data speak in favour of development of differentiation therapy based on p53-dependent differentiation pathways.
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| 8. |
- Drott, Kristina, et al.
(författare)
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Valproate in combination with rituximab and CHOP as first-line therapy in diffuse large B-cell lymphoma (VALFRID)
- 2018
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 2:12, s. 1386-1392
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Tidskriftsartikel (refereegranskat)abstract
- The aims of the present study were to establish the maximally tolerated dose (MTD) of the histone deacetylase inhibitor valproate together with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with diffuse large B-cell lymphoma (DLBCL). A phase 1 dose escalation study of valproate together with R-CHOP followed by a dose expansion study using the established MTD of valproate was performed. MTD of valproate together with R-CHOP was established at 60 mg/kg per day, as higher doses resulted in auditory adverse events (AEs). In the study population, 2-year progression-free survival was 84.7% (95% confidence interval [CI], 73.2%-98%). The 2-year overall survival (OS) was 96.8% (n = 31; 95% CI, 90.8%-100%). These data were compared with 2 risk-factor matched populations of R-CHOP-treated patients from the Swedish Lymphoma Registry (cohort A, n = 330 and B, n = 165). As compared with the matched cohorts, we observed a statistically significant (P = .034 and 0.028, respectively) beneficial effect of the addition of valproate to R-CHOP on the OS in the studied population. In conclusion, addition of valproate to R-CHOP is a feasible strategy in first-line treatment of DLBCL. The proposed phase 2 dose is 60 mg/kg per day together with prednisone. Auditory AEs were unexpected and warrant close monitoring. Our findings suggest that drugs that target histone deacetylation may add benefit and are tolerable when combined with standard R-CHOP in DLBCL. The phase 1 trial was registered at www.clinicaltrials.gov as #NCT01622439.
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| 9. |
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| 10. |
- 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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| 11. |
- 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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| 12. |
- 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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| 13. |
- Mörth, Charlott
(författare)
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Clinical and tumour biology studies of Diffuse Large B-cell Lymphoma : with emphasis on comorbidity, toxicity and outcome
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diffuse large B-cell lymphoma (DLBCL) is curable in around 70% when treated with standard immunochemotherapy R- CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). Treatment related toxicity affecting survivors is a clinical problem as well as comorbidities influencing the possibility to give adequate treatment. The relevance of follow-up time and follow-up measures can be debated, follow-up time in Sweden has been reduced to two years due to studies showing an OS survival comparable to standard population among DLBCL achieving EFS24.The main objective of this thesis is to study known side-effects of treatment and comorbidities and explore outcome in DLBCL in order to improve clinical treatment and follow-up decisions. In Paper I we explored whether the omission of vincristine (VCR) due to neurotoxicity affect outcome (DFS,OS). In 541 patients omission of VCR was made in 95 (17.6%). There was no impact on outcome measures in the whole cohort irrespective of treatment cycle for the omission nor was there a difference in the elderly (≥70 years) group. In Paper II we studied the occurrence of different autoimmune disorders (AID) in 612 DLBCL and analysed whether AID affects treatment outcome. We found a high occurrence of AID among DLBCL patients (17.3%) compared to the general population (3-10%). AID did not affect EFS/LSS or OS in the whole cohort but women with B-cell response AID had a worse OS compared to other women (p=0.013). In Paper III we established event free survival at 24 months (EFS24) in a Swedish DLBCL cohort and analysed factors governing OS and compared OS with an age and gender matched standard population. 71.6% achieved EFS24 and OS was marginally lower than the standard population. Age was the only factor affecting OS in multivariate analysis and EFS24 patients<60 years had a comparable OS to the standard population. In older ages (>60years) there was a trend for worse OS driven by a significant difference in OS among those 60-69 years. Among DLBCL achieving EFS24, 22.4% died of cardiovascular disease and 16% from other malignancies. In Paper IV we explored whether advanced serum protein analysis can be used to measure doxorubicin (DXR) related cardiac/cardiovascular (CVD) disease in DLBCL patients. We found two proteins, SPON-1 associated with CVD at diagnosis and IL-1RT1 associated with emerging CVD after treatment. Compared to the general population and to a matched cohort DLBCL patients had a high occurrence of CVD at diagnosis, 33.4%. After treatment 22.6% developed CVD.
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| 14. |
- 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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| 15. |
- 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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| 16. |
- 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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| 17. |
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| 18. |
- 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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| 19. |
- Scialdone, Annarita, et al.
(författare)
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Depletion of the transcriptional coactivators CREB-binding protein or EP300 downregulates CD20 in diffuse large B-cell lymphoma cells and impairs the cytotoxic effects of anti-CD20 antibodies
- 2019
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Ingår i: Experimental Hematology. - : Elsevier BV. - 0301-472X .- 1873-2399. ; 79, s. 1-46
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Tidskriftsartikel (refereegranskat)abstract
- Monoclonal antibodies targeting CD20 are central in the treatment of B-cell lymphomas. In diffuse large B-cell lymphoma (DLBCL), inactivating mutations of the histone acetyltransferases CREB-binding protein (CBP) and EP300 are common. Moreover, knockdown of CBP in DLBCL has been shown to result in aberrant transcriptional silencing. Expression of CD20 is sensitive to epigenetic manipulation, and histone deacetylase inhibitors have been found to potentiate treatment with anti-CD20 antibodies. Therefore, we studied the role of CBP and EP300 depletion on CD20 expression and effects of the anti-CD20 antibodies rituximab and obinutuzumab in DLBCL cells. Levels of CBP and EP300 were reduced by shRNA in the germinal centre-derived diffuse large B-cell lymphoma cell line SU-DHL4. The levels of CD20 mRNA and protein were determined by quantitative polymerase chain reaction, Western blot, and flow cytometry. Binding of the transcription factors PU.1 and FOXO1 to the CD20 promoter was determined by chromatin immunoprecipitation coupled with quantitative polymerase chain reaction. Response to the monoclonal anti-CD20 antibodies rituximab and obinutuzumab in CBP- or EP300-depleted cells was assessed by complement-dependent cell death, direct cell death, and antibody-dependent cellular cytotoxicity (ADCC). Our results suggest that depletion of CBP and EP300 levels leads to a strong reduction of CD20 expression, accompanied by reduced binding of PU.1 to the CD20 promoter. In CBP-depleted, but not EP300-depleted cells, increased binding of FOXO1 to the CD20 promoter was observed. Interestingly, CBP or EP300 depletion leads to decreased complement-dependent cell death and direct cell death in response to rituximab and obinutuzumab, which was most pronounced in response to rituximab in CBP-depleted cells. Our data suggest that inactivating mutations of CBP, and to a lesser extent EP300, may impair the response to anti-CD20 antibodies. However, these observations should be analyzed in future clinical trials.
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| 20. |
- Scialdone, Annarita, et al.
(författare)
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The HDAC inhibitor valproate induces a bivalent status of the CD20 promoter in CLL patients suggesting distinct epigenetic regulation of CD20 expression in CLL in vivo
- 2017
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 8:23, s. 37409-37422
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Tidskriftsartikel (refereegranskat)abstract
- Treatment with anti-CD20 antibodies is only moderately efficient in chronic lymphocytic leukemia (CLL), a feature which has been explained by the inherently low CD20 expression in CLL. It has been shown that CD20 is epigenetically regulated and that histone deacetylase inhibitors (HDACis) can increase CD20 expression in vitro in CLL. To assess whether HDACis can upregulate CD20 also in vivo in CLL, the HDACi valproate was given to three del13q/NOTCH1wt CLL patients and CD20 levels were analysed (the PREVAIL study). Valproate treatment resulted in expected global activating histone modifications suggesting HDAC inhibitory effects. However, although valproate induced expression of CD20 mRNA and protein in the del13q/ NOTCH1wt I83-E95 CLL cell line, no such effects were observed in the patients studied. In contrast to the cell line, in patients valproate treatment resulted in transient recruitment of the transcriptional repressor EZH2 to the CD20 promoter, correlating to an increase of the repressive histone mark H3K27me3. This suggests that valproate-mediated induction of CD20 may be hampered by EZH2 mediated H3K27me3 in vivo in CLL. Moreover, valproate treatment resulted in induction of EZH2 and global H3K27me3 in patient cells, suggesting transcriptionally repressive effects of valproate in CLL. Our results suggest new in vivo mechanisms of HDACis which may have implications on the design of future clinical trials in B-cell malignancies.
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| 21. |
- Ullmark, Tove, et al.
(författare)
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Anti-apoptotic quinolinate phosphoribosyltransferase (QPRT) is a target gene of Wilms' tumor gene 1 (WT1) protein in leukemic cells
- 2017
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 0006-291X. ; 482:4, s. 802-807
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Tidskriftsartikel (refereegranskat)abstract
- Wilms' tumor gene 1 (WT1) is a zinc finger transcription factor that has been implicated as an oncogene in leukemia and several other malignancies. When investigating possible gene expression network partners of . WT1 in a large acute myeloid leukemia (AML) patient cohort, one of the genes with the highest correlation to . WT1 was quinolinate phosphoribosyltransferase (QPRT), a key enzyme in the . de novo nicotinamide adenine dinucleotide (NAD+) synthesis pathway. To investigate the possible relationship between . WT1 and . QPRT, we overexpressed . WT1 in hematopoietic progenitor cells and cell lines, resulting in an increase of . QPRT expression. WT1 knock-down gave a corresponding decrease in . QPRT gene and protein expression. Chromatin-immunoprecipitation revealed WT1 binding to a conserved site in the first intron of the . QPRT gene. Upon overexpression in leukemic K562 cells, QPRT conferred partial resistance to the anti-leukemic drug imatinib, indicating possible anti-apoptotic functions, consistent with previous reports on glioma cells. Interestingly, the rescue effect of QPRT overexpression was not correlated to increased NAD + levels, suggesting NAD + independent mechanisms. We conclude that . QPRT, encoding a protein with anti-apoptotic properties, is a novel and direct target gene of WT1 in leukemic cells.
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| 22. |
- Ullmark, Tove, et al.
(författare)
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Distinct global binding patterns of the Wilms' tumor gene 1 (WT1) -KTS and +KTS isoforms in leukemic cells
- 2017
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 102:2, s. 336-345
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Tidskriftsartikel (refereegranskat)abstract
- The zinc finger transcription factor Wilms' tumor gene 1 (WT1) acts as an oncogene in acute myeloid leukemia. A naturally occurring alternative splice event between zinc fingers three and four, removing or retaining three amino acids (+/-KTS), is believed to change the DNA binding affinity of WT1, although there are conflicting data regarding the binding affinity and motifs of the different isoforms. Increased expression of WT1 -KTS at the expense of WT1 +KTS isoform associates with poor prognosis in acute myeloid leukemia. We determined the genome-wide binding pattern of WT1 -KTS and WT1 +KTS in leukemic K562 cells by chromatin immunoprecipitation and deep sequencing (ChIP-seq). Motif discovery revealed distinct binding motifs for the isoforms, some of which have been previously reported as WT1 binding sites. We discovered that the WT1 -KTS isoform predominantly binds close to transcription start sites and to enhancers, in a similar fashion to other transcription factors, whereas WT1 +KTS binding is rather enriched within gene bodies. We observed a significant overlap between WT1 -KTS and WT1 +KTS target genes, despite the binding sites being distinct. Motif discovery revealed distinct binding motifs for the isoforms, some of which have been previously reported as WT1 binding sites. Additional analyses showed that both WT1 -KTS and WT1 +KTS target genes are more likely to be transcribed than non-targets, and are involved in cell proliferation, cell death, and development. Our study provides evidence that WT1 -KTS and WT1 +KTS share target genes yet still bind distinct locations, indicating isoform-specific regulation in transcription of genes related to cell proliferation and differentiation, consistent with involvement of WT1 in acute myeloid leukemia.
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