| 1. |
- Abolhalaj, Milad, et al.
(författare)
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Transcriptional profiling demonstrates altered characteristics of CD8 + cytotoxic T-cells and regulatory T-cells in TP53-mutated acute myeloid leukemia
- 2022
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Ingår i: Cancer Medicine. - : Wiley. - 2045-7634. ; 11:15, s. 3023-3032
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Tidskriftsartikel (refereegranskat)abstract
- Background: Acute myeloid leukemia (AML) patients have limited effect from T-cell-based therapies, such as PD-1 and CTLA-4 blockade. However, recent data indicate that AML patients with TP53 mutation have higher immune infiltration and other immunomodulatory therapies could thus potentially be effective. Here, we performed the transcriptional analysis of distinct T-cell subpopulations from TP53-mutated AML to identify gene expression signatures suggestive of altered functional properties.Methods: CD8+ cytotoxic T lymphocytes (CTLs), conventional helper T cells (Th), and regulatory T cells (Tregs) were sorted from peripheral blood of AML patients with TP53 mutation (n = 5) and healthy donors (n = 3), using FACS, and the different subpopulations were subsequently subjected to RNA-sequencing. Differentially expressed genes were identified and gene set enrichment analysis (GSEA) was performed to outline altered pathways and exhaustion status. Also, expression levels for a set of genes encoding established and emerging immuno-oncological targets were defined.Results: The results showed altered transcriptional profiles for each of the T-cell subpopulations from TP53-mutated AML as compared to control subjects. IFN-α and IFN-γ signaling were stronger in TP53-mutated AML for both CTLs and Tregs. Furthermore, in TP53-mutated AML as compared to healthy controls, Tregs showed gene expression signatures suggestive of metabolic adaptation to their environment, whereas CTLs exhibited features of exhaustion/dysfunction with a stronger expression of TIM3 as well as enrichment of a gene set related to exhaustion.Conclusions: The results provide insights on mechanisms underlying the inadequate immune response to leukemic cells in TP53-mutated AML and open up for further exploration toward novel treatment regimens for these patients.
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| 2. |
- Sandén, Carl, et al.
(författare)
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Clonal competition within complex evolutionary hierarchies shapes AML over time
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Clonal heterogeneity and evolution has major implications for disease progression and relapse in acute myeloid leukemia (AML). To model clonal dynamics in vivo, we serially transplanted 23 AML cases to immunodeficient mice and followed clonal composition for up to 15 months by whole-exome sequencing of 84 xenografts across two generations. We demonstrate vast changes in clonality that both progress and reverse over time, and define five patterns of clonal dynamics: Monoclonal, Stable, Loss, Expansion and Burst. We also show that subclonal expansion in vivo correlates with a more adverse prognosis. Furthermore, clonal expansion enabled detection of very rare clones with AML driver mutations that were undetectable by sequencing at diagnosis, demonstrating that the vast majority of AML cases harbor multiple clones already at diagnosis. Finally, the rise and fall of related clones enabled deconstruction of the complex evolutionary hierarchies of the clones that compete to shape AML over time.
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| 3. |
- Ågerstam, Helena, et al.
(författare)
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Antibodies targeting human IL1RAP (IL1R3) show therapeutic effects in xenograft models of acute myeloid leukemia.
- 2015
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 112:34, s. 10786-10791
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Tidskriftsartikel (refereegranskat)abstract
- Acute myeloid leukemia (AML) is associated with a poor survival rate, and there is an urgent need for novel and more efficient therapies, ideally targeting AML stem cells that are essential for maintaining the disease. The interleukin 1 receptor accessory protein (IL1RAP; IL1R3) is expressed on candidate leukemic stem cells in the majority of AML patients, but not on normal hematopoietic stem cells. We show here that monoclonal antibodies targeting IL1RAP have strong antileukemic effects in xenograft models of human AML. We demonstrate that effector-cell-mediated killing is essential for the observed therapeutic effects and that natural killer cells constitute a critical human effector cell type. Because IL-1 signaling is important for the growth of AML cells, we generated an IL1RAP-targeting antibody capable of blocking IL-1 signaling and show that this antibody suppresses the proliferation of primary human AML cells. Hence, IL1RAP can be efficiently targeted with an anti-IL1RAP antibody capable of both achieving antibody-dependent cellular cytotoxicity and blocking of IL-1 signaling as modes of action. Collectively, these results provide important evidence in support of IL1RAP as a target for antibody-based treatment of AML.
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| 4. |
- Ågerstam, Helena, et al.
(författare)
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IL1RAP antibodies block IL-1-induced expansion of candidate CML stem cells and mediate cell killing in xenograft models.
- 2016
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 128:23, s. 2683-2693
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Tidskriftsartikel (refereegranskat)abstract
- Chronic myeloid leukemia (CML) is currently treated with tyrosine kinase inhibitors, but these do not effectively eliminate the CML stem cells. As a consequence, CML stem cells persist and cause relapse in most patients upon drug discontinuation. Furthermore, no effective therapy exists for the advanced stages of the disease. Interleukin-1 receptor accessory protein (IL1RAP; IL1R3) is a coreceptor of interleukin-1 receptor type 1 and has been found upregulated on CML stem cells. Here, we show that primitive (CD34(+)CD38(-)) CML cells, in contrast to corresponding normal cells, express a functional interleukin-1 (IL-1) receptor complex and respond with NF-κB activation and marked proliferation in response to IL-1. IL1RAP antibodies that inhibit IL-1 signaling could block these effects. In vivo administration of IL1RAP antibodies in mice transplanted with chronic and blast phase CML cells resulted in therapeutic effects mediated by murine effector cells. These results provide novel insights into the role of IL1RAP in CML and a strong rationale for the development of an IL1RAP antibody therapy to target residual CML stem cells.
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| 5. |
- Albertsson, Per, 1956, et al.
(författare)
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Morbidity and use of medical resources in patients with chest pain and normal or near-normal coronary arteries.
- 1997
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Ingår i: The American journal of cardiology. - : Excerpta Medica, Inc.. - 0002-9149 .- 1879-1913. ; 79:3, s. 299-304
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Tidskriftsartikel (refereegranskat)abstract
- To evaluate morbidity and use of medical resources in patients with chest pain and normal or near-normal coronary angiograms: 2,639 consecutive patients who underwent coronary angiograms due to chest pain were registered. Two years thereafter all patients who showed normal or near-normal coronary angiograms were approached with a questionnaire regarding hospitalization during the last 4 years (2 years before and 2 years after angiography). All medical files were also examined. Of the patients who underwent angiography, 163 (6%) had no significant stenoses, and of these, 113 showed complete normal angiograms and 50 showed mild (i.e. <50%) stenoses. During the 2 years before diagnostic angiogram, 66% of the patients were hospitalized compared with only 35% during 2 years after angiography (p <0.001). The reduction in hospitalization was due to curtailed utilization of medical resources for cardiac reasons; mean days in hospital was 6.6 days before angiography versus 2.8 days after (p <0.001). There were no significant differences in hospitalization when comparing patients with mild stenoses and completely normal angiograms. There were, furthermore, no differences between patients with positive or negative exercise tests. Thus, the need for hospitalization is significantly reduced after a diagnostic angiogram reveals normal or near-normal coronary arteries.
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| 6. |
- Ardestani, Shahrzad, et al.
(författare)
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B2SHARE : An open eScience data sharing platform
- 2015
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Ingår i: Proceedings - 11th IEEE International Conference on eScience. - : IEEE. ; , s. 448-453
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Konferensbidrag (refereegranskat)abstract
- Scientific data sharing is becoming an essential service for data driven science and can significantly improve the scientific process by making reliable, and trustworthy data available. Thereby reducing redundant work, and providing insights on related research and recent advancements. For data sharing services to be useful in the scientific process, they need to fulfill a number of requirements that cover not only discovery, and access to data. But to ensure the integrity, and reliability of published data as well. B2SHARE, developed by the EUDAT project, provides such a data sharing service to scientific communities. For communities that wish to download, install and maintain their own service, it is also available as software. B2SHARE is developed with a focus on user-friendliness, reliability, and trustworthiness, and can be customized for different organizations and use-cases. In this paper we discuss the design, architecture, and implementation of B2SHARE. We show its usefulness in the scientific process with some case studies in the biodiversity field.
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| 7. |
- Enquist, Johan, et al.
(författare)
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Kinin-Stimulated B1 Receptor Signaling Depends on Receptor Endocytosis Whereas B2 Receptor Signaling Does Not.
- 2014
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Ingår i: Neurochemical Research. - : Springer Science and Business Media LLC. - 1573-6903 .- 0364-3190. ; 39:6, s. 1037-1047
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Tidskriftsartikel (refereegranskat)abstract
- Kinins are potent pro-inflammatory peptides that act through two G protein-coupled receptor subtypes, B1 (B1R) and B2 (B2R). Kinin-stimulated B2R signaling is often transient, whereas B1R signaling is sustained. This was confirmed by monitoring agonist-stimulated intracellular Ca(2+) mobilization in A10 smooth muscle cells expressing human wild-type B2R and B1R. We further studied the role of receptor membrane trafficking in receptor-mediated phosphoinositide (PI) hydrolysis in model HEK293 cell lines stably expressing the receptors. Treatment of cells with brefeldin A, to inhibit maturation of de novo synthesized receptors, or hypertonic sucrose, to inhibit receptor endocytosis, showed that the basal cell surface receptor turnover was considerably faster for B1R than for B2R. Inhibition of endocytosis, which stabilized B1R on the cell surface, inhibited B1R signaling, whereas B2R signaling was not perturbed. Signaling by a B1R construct in which the entire C-terminal domain was deleted remained sensitive to inhibition of receptor endocytosis, whereas signaling by a B1R construct in which this domain was substituted with the corresponding domain in B2R was not sensitive. B2R and B1R co-expression, which also appeared to stabilize B1R on the cell surface, presumably by receptor hetero-dimerization, also inhibited B1R signaling, whereas B2R signaling was slightly enhanced. Furthermore, the B2R-specific agonist bradykinin (BK) directed both receptors through a common endocytic pathway, whereas the B1R-specific agonist Lys-desArg(9)-BK was unable to do so. These results suggest that B1R-mediated PI hydrolysis depends on a step in receptor endocytosis, whereas B2R-mediated PI hydrolysis does not. We propose that B1R uses at least part of the endocytic machinery to sustain agonist-promoted signaling.
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| 8. |
- Erjefält, Jonas S., et al.
(författare)
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Diffuse alveolar damage patterns reflect the immunological and molecular heterogeneity in fatal COVID-19
- 2022
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Ingår i: EBioMedicine. - : Elsevier BV. - 2352-3964. ; 83
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Tidskriftsartikel (refereegranskat)abstract
- Background: Severe COVID-19 lung disease exhibits a high degree of spatial and temporal heterogeneity, with different histological features coexisting within a single individual. It is important to capture the disease complexity to support patient management and treatment strategies. We provide spatially decoded analyses on the immunopathology of diffuse alveolar damage (DAD) patterns and factors that modulate immune and structural changes in fatal COVID-19. Methods: We spatially quantified the immune and structural cells in exudative, intermediate, and advanced DAD through multiplex immunohistochemistry in autopsy lung tissue of 18 COVID-19 patients. Cytokine profiling, viral, bacteria, and fungi detection, and transcriptome analyses were performed. Findings: Spatial DAD progression was associated with expansion of immune cells, macrophages, CD8+ T cells, fibroblasts, and (lymph)angiogenesis. Viral load correlated positively with exudative DAD and negatively with disease/hospital length. In all cases, enteric bacteria were isolated, and Candida parapsilosis in eight cases. Cytokines correlated mainly with macrophages and CD8+T cells. Pro-coagulation and acute repair were enriched pathways in exudative DAD whereas intermediate/advanced DAD had a molecular profile of elevated humoral and innate immune responses and extracellular matrix production. Interpretation: Unraveling the spatial and molecular immunopathology of COVID-19 cases exposes the responses to SARS-CoV-2-induced exudative DAD and subsequent immune-modulatory and remodeling changes in proliferative/advanced DAD that occur side-by-side together with secondary infections in the lungs. These complex features have important implications for disease management and the development of novel treatments. Funding: CNPq, Bill and Melinda Gates Foundation, HC-Convida, FAPESP, Regeneron Pharmaceuticals, and the Swedish Heart & Lung Foundation.
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| 9. |
- Hultmark, Simon, et al.
(författare)
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Combinatorial molecule screening identifies a novel diterpene and the BET inhibitor CPI-203 as differentiation inducers of primary acute myeloid leukemia cells
- 2021
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 1592-8721 .- 0390-6078. ; 106:10
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Tidskriftsartikel (refereegranskat)abstract
- Combination treatment has proven effective for patients with acute promyelocytic leukemia, exemplifying the importance of therapy targeting multiple components of oncogenic regulation for a successful outcome. However, recent studies have shown that the mutational complexity of acute myeloid leukemia (AML) precludes the translation of molecular targeting into clinical success. Here as a complement to genetic profiling, we used unbiased, combinatorial in vitro drug screening to identify pathways that drive AML and to develop personalized combinatorial treatments. First, we screened 513 natural compounds on primary AML cells and identified a novel diterpene (H4) that preferentially induced differentiation of FLT3 wild-type AMLs, while FLT3-ITD/mutations conferred resistance. The responding samples to H4, displayed increased expression of myeloid markers, a clear decrease in the nuclear-cytoplasmic ratio and the potential of re-activation of the monocytic transcriptional program reducing leukemia propagation in vivo. By combinatorial screening using H4 and molecules with defined targets, we demonstrated that H4 induces differentiation by the activation of protein kinase C (PKC) signaling pathway, and in line with this, activates PKC phosphorylation and translocation of PKC to the cell membrane. Furthermore, the combinatorial screening identified a bromo- and extra-terminal domain (BET) inhibitor that could further improve H4-dependent leukemic differentiation in FLT3 wild-type monocytic AML. Taken together, this illustrates the value of an unbiased and multiplex screening platform for developing combinatorial therapeutic approaches for AML.
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| 10. |
- Hvidtfeldt, Morten, et al.
(författare)
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Airway hyperresponsiveness reflects corticosteroid-sensitive mast cell involvement across asthma phenotypes
- 2023
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749. ; 152:1, s. 4-116
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Tidskriftsartikel (refereegranskat)abstract
- Background: Airway hyperresponsiveness is a hallmark of asthma across asthma phenotypes. Airway hyperresponsiveness to mannitol specifically relates to mast cell infiltration of the airways, suggesting inhaled corticosteroids to be effective in reducing the response to mannitol, despite low levels of type 2 inflammation. Objective: We sought to investigate the relationship between airway hyperresponsiveness and infiltrating mast cells, and the response to inhaled corticosteroid treatment. Methods: In 50 corticosteroid-free patients with airway hyperresponsiveness to mannitol, mucosal cryobiopsies were obtained before and after 6 weeks of daily treatment with 1600 μg of budesonide. Patients were stratified according to baseline fractional exhaled nitric oxide (FENO) with a cutoff of 25 parts per billion. Results: Airway hyperresponsiveness was comparable at baseline and improved equally with treatment in both patients with FENO-high and FENO-low asthma: doubling dose, 3.98 (95% CI, 2.49-6.38; P < .001) and 3.85 (95% CI, 2.51-5.91; P < .001), respectively. However, phenotypes and distribution of mast cells differed between the 2 groups. In patients with FENO-high asthma, airway hyperresponsiveness correlated with the density of chymase-high mast cells infiltrating the epithelial layer (ρ, −0.42; P = .04), and in those with FENO-low asthma, it correlated with the density in the airway smooth muscle (ρ, −0.51; P = .02). The improvement in airway hyperresponsiveness after inhaled corticosteroid treatment correlated with a reduction in mast cells, as well as in airway thymic stromal lymphopoietin and IL-33. Conclusions: Airway hyperresponsiveness to mannitol is related to mast cell infiltration across asthma phenotypes, correlating with epithelial mast cells in patients with FENO-high asthma and with airway smooth muscle mast cells in patients with FENO-low asthma. Treatment with inhaled corticosteroids was effective in reducing airway hyperresponsiveness in both groups.
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| 11. |
- Hvidtfeldt, Morten, et al.
(författare)
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Mucosal cryobiopsies : a new method for studying airway pathology in asthma
- 2022
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Ingår i: ERJ open research. - : European Respiratory Society (ERS). - 2312-0541. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Background In vivo studies of airway pathology in obstructive lung disease are limited by poor quality of specimens obtained with forceps. Obtainment of cryobiopsies has increased diagnostic yield in cancer and interstitial lung disease but has not been used in patients with asthma. In a recent pilot study, we found mucosal cryobiopsies to be larger and more intact than conventional forceps biopsies. The aim of the present study was to compare quality and safety of mucosal cryobiopsies versus conventional forceps biopsies in patients with asthma. Methods Endobronchial biopsies were obtained with forceps and cryoprobe from patients with asthma not currently treated with inhaled steroids and evaluated histologically. Results A total of 240 cryobiopsies and 288 forceps biopsies were obtained from 48 patients. Bleeding from the biopsy site was common but self-limiting. No major complications related to the procedure were seen. Cryobiopsy cross areas were four times larger compared with forceps. Stretches of intact epithelium were detected in all cryobiopsies compared to 33% in forceps biopsies. Further, the length of intact epithelium was on average four times longer in the cryobiopsies. Importantly, there was a good preservation of both antigens and mRNA in the cryobiopsies ensuring a suitability and robustness for immunohistochemistry and in situ hybridisation. Conclusion Obtainment of mucosal cryobiopsies in patients with asthma is safe and yields biopsies that are significantly larger and morphologically better preserved compared with traditional forceps biopsies. The cryotechnique thus seems to be a promising tool for future in vivo studies of airway pathology.
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| 12. |
- Iderberg, Hanna, et al.
(författare)
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Predicting clinical outcome and length of sick leave after surgery for lumbar spinal stenosis in Sweden : a multi-register evaluation
- 2019
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Ingår i: European spine journal. - : Springer Science and Business Media LLC. - 0940-6719 .- 1432-0932. ; 28:6, s. 1423-1432
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Lumbar spinal stenosis (LSS) can be surgically treated, with variable outcome. Studies have linked socioeconomic factors to outcome, but no nation-wide studies have been performed. This register-based study, including all patients surgically treated for LSS during 2008-2012 in Sweden, aimed to determine predictive factors for the outcome of surgery.Methods: Clinical and socioeconomic factors with impact on outcome in LSS surgery were identified in several high-coverage registers, e.g., the national quality registry for spine surgery (Swespine, FU-rate 70-90%). Multivariate regression analyses were conducted to assess their effect on outcome. Two patient-reported outcome measures, Global Assessment of leg pain (GA) and the Oswestry Disability Index (ODI), as well as length of sick leave after surgery were analyzed.Results: Clinical and socioeconomic factors significantly affected health outcome (both GA and ODI). Some predictors of a good outcome (ODI) were: being born in the EU, reporting no back pain at baseline, a high disposable income and a high educational level. Some factors predicting a worse outcome were previous surgery, having had back pain more than 2years, having comorbidities, being a smoker, being on social welfare and being unemployed.Conclusions: The study highlights the relevance of adding socioeconomic factors to clinical factors for analysis of patient-reported outcomes, although the causal pathway of most predictors' impact is unknown. These findings should be further investigated in the perspective of treatment selection for individual LSS patients. The study also presents a foundation of case mix algorithms for predicting outcome of surgery for LSS.
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| 13. |
- Landberg, Niklas, et al.
(författare)
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CD36 defines primitive chronic myeloid leukemia cells less responsive to imatinib but vulnerable to antibody-based therapeutic targeting
- 2018
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 103:3, s. 447-455
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Tidskriftsartikel (refereegranskat)abstract
- Tyrosine kinase inhibitors (TKIs) are highly effective for the treatment of chronic myeloid leukemia (CML), but very few patients are cured. The major drawbacks regarding TKIs are their low efficacy in eradicating the leukemic stem cells responsible for disease maintenance and relapse upon drug cessation. Herein, we performed ribonucleic acid sequencing of flow-sorted primitive (CD34+CD38low) and progenitor (CD34+CD38+) chronic phase CML cells, and identified transcriptional upregulation of 32 cell surface molecules relative to corresponding normal bone marrow cells. Focusing on novel markers with increased expression on primitive CML cells, we confirmed upregulation of the scavenger receptor CD36 and the leptin receptor by flow cytometry. We also delineate a subpopulation of primitive CML cells expressing CD36 that is less sensitive to imatinib treatment. Using CD36 targeting antibodies, we show that the CD36 positive cells can be targeted and killed by antibody-dependent cellular cytotoxicity. In summary, CD36 defines a subpopulation of primitive CML cells with decreased imatinib sensitivity that can be effectively targeted and killed using an anti-CD36 antibody.
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| 14. |
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| 15. |
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| 16. |
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| 17. |
- Rydh, Carl Johan, 1971, et al.
(författare)
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Energy analysis of batteries in photovoltaic systems Part II. Energy return factors and overall battery efficiencies
- 2005
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Ingår i: Energy Conversion and Management. - : Elsevier BV. - 0196-8904. ; 46:11-12, s. 1980-2000
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Tidskriftsartikel (refereegranskat)abstract
- Energy return factors and overall energy efficiencies are calculated for a stand-alone photovoltaic (PV)-battery system. Eight battery technologies are evaluated: lithium-ion (nickel), sodium-sulphur, nickel-cadmium, nickel-metal hydride, lead-acid, vanadium-redox, zinc-bromine and polysulphide-bromide. With a battery energy storage capacity three times higher than the daily energy output, the energy return factor for the PV-battery system ranges from 2.2 to 10 in our reference case. For a PV-battery system with a service life of 30 yr, this corresponds to energy payback times between 2.5 and 13 yr. The energy payback time is 1.8-3.3 yr for the PV array and 0.72-10 yr for the battery, showing the energy related significance of batteries and the large variation between different technologies. In extreme cases, energy return factors below one occur, implying no net energy output. The overall battery efficiency, including not only direct energy losses during operation but also energy requirements for production and transport of the charger, the battery and the inverter, is 0.41-0.80. For some batteries, the overall battery efficiency is significantly lower than the direct efficiency of the charger, the battery and the inverter (0.50-0.85). The ranking order of batteries in terms of energy efficiency, the relative importance of different battery parameters and the optimal system design and operation (e.g. the use of air conditioning) are, in many cases, dependent on the characterisation of the energy background system and on which type of energy efficiency measure is used (energy return factor or overall battery efficiency). © 2004 Elsevier Ltd. All rights reserved.
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| 18. |
- 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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| 19. |
- Sandén, Carl
(författare)
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Molecular Mechanisms of the DEK Protein in Leukemia
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The DEK gene is upregulated in a growing number of cancers and translocated to form the DEK-NUP214 fusion gene in a subset of acute myeloid leukemia. In this thesis, we studied the cellular and molecular functions of the DEK and DEK-NUP214 proteins. We found that the expression of DEK is increased by the leukemia-associated fusion protein NUP98-HOXA9, suggesting that DEK may be a downstream mediator of its leukemogenic function. We also determined the genome-wide binding of the DEK protein, showing that DEK binds specifically to the trans-cription start sites of predominantly highly and ubiquitously expressed genes. Furthermore, we demonstrated that DEK can serve to either promote or repress the transcription of these genes. Finally, we discovered that the DEK-NUP214 fusion protein promotes cellular proliferation through increased expression of mTOR and enhanced activity of mTORC1. Pharmacological inhibition of mTOR selectively reversed the proliferative effect, suggesting that patients with the fusion gene may benefit from treatment with mTOR inhibitors. These findings elucidate the roles of DEK and DEK-NUP214 in cancer with implications for the treatment of the associated malignancies.
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| 20. |
- Sandén, Carl, et al.
(författare)
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The DEK oncoprotein and its emerging roles in gene regulation.
- 2015
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Ingår i: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 29:8, s. 1632-1636
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Forskningsöversikt (refereegranskat)abstract
- The DEK oncogene is highly expressed in cells from most human tissues and overexpressed in a large and growing number of cancers. It also fuses with the NUP214 gene to form the DEK-NUP214 fusion gene in a subset of acute myeloid leukemia. Originally characterized as a member of this translocation, DEK has since been implicated in epigenetic and transcriptional regulation but its role in these processes is still elusive and intriguingly complex. Similarly multifaceted is its contribution to cellular transformation, affecting multiple cellular processes such as self-renewal, proliferation, differentiation, senescence and apoptosis. Recently, the roles of the DEK and DEK-NUP214 proteins have been elucidated by global analysis of DNA binding and gene expression as well as multiple functional studies. This review outlines recent advances in the understanding of the basic functions of the DEK protein and its role in leukemogenesis.Leukemia accepted article preview online, 13 March 2015. doi:10.1038/leu.2015.72.
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| 21. |
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| 22. |
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| 23. |
- Siddhuraj, Premkumar, et al.
(författare)
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Lung Mast Cells Have a High Constitutive Expression of Carboxypeptidase A3 mRNA That Is Independent from Granule-Stored CPA3
- 2021
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Ingår i: Cells. - : MDPI AG. - 2073-4409. ; 10:2
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Tidskriftsartikel (refereegranskat)abstract
- The mast cell granule metalloprotease CPA3 is proposed to have important tissue homeostatic functions. However, the basal CPA3 mRNA and protein expression among mast cell populations has remained poorly investigated. Using a novel histology-based methodology that yields quantitative data on mRNA and protein expression at a single-cell level, the present study maps CPA3 mRNA and protein throughout the MCT and MCTC populations in healthy skin, gut and lung tissues. MCTC cells had both a higher frequency of CPA3 protein-containing cells and a higher protein-staining intensity than the MCT population. Among the tissues, skin MCs had highest CPA3 protein intensity. The expression pattern at the mRNA level was reversed. Lung mast cells had the highest mean CPA3 mRNA staining. Intriguingly, the large alveolar MCT population, that lack CPA3 protein, had uniquely high CPA3 mRNA intensity. A broader multi-tissue RNA analysis confirmed the uniquely high CPA3 mRNA quantities in the lung and corroborated the dissociation between chymase and CPA3 at the mRNA level. Taken together, our novel data suggest a hitherto underestimated contribution of mucosal-like MCT to baseline CPA3 mRNA production. The functional consequence of this high constitutive expression now reveals an important area for further research.
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| 24. |
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| 25. |
- Thodelius, Charlotta, et al.
(författare)
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Kriminologiska perspektiv på dödligt skolvåld
- 2021
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Bok (refereegranskat)abstract
- Dödligt skolvåld ingår i serien Kriminologiska perspektiv på ... och belyser svenska händelser av dödligt eller potentiellt dödligt skolvåld. Ger en samlad bild av dödligt skolvåld i Sverige.- Kombinerar rättsligt material och vetenskaplig litteratur.- Kan användas för att belysa likartade händelser, som attacker i köpcentrum eller synagogor. - Visar hur liknande händelser kan förhindras – och hur man kan begränsa följderna när de väl inträffar.Boken är lämplig för utbildning inom exempelvis kriminologi, juridik, psykologi, sociologi och socialt eller polisiärt arbete. Den kan med fördel användas som fortbildning för professionella inom rättsväsende och brottsförebyggande arbete.
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| 26. |
- 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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| 27. |
- Ullmark, Tove, et al.
(författare)
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Global binding pattern of the Wilms' tumor gene 1 (WT1) +17AA -KTS isoform in leukemic cells
- 2016
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Ingår i: Cancer Research. - 1538-7445. ; 76:14 Suppl.
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Konferensbidrag (refereegranskat)abstract
- The aim of this study was to investigate the global DNA-binding pattern of Wilms' tumor gene 1 (WT1) in leukemic cells. Clinical and preclinical data indicate the zinc finger transcription factor WT1 as an oncogene, but the full target gene repertoire of WT1 in leukemic cells has not been previously characterized. The -KTS isoforms (excluding the three amino acid (KTS) insert between zinc finger three and four) are considered as the most efficient DNA-binders. Among these, the 17AA isoform (including 17 amino acids encoded by exon 5) is the most abundant one. To specifically analyze the DNA-binding of WT1(+17AA/-KTS) in leukemic cells, we generated a K562 clone that stably expressed BIO-tagged WT1(+17AA/-KTS), as well as the biotinylating enzyme Bir A. From the cells chromatin immunoprecipitation (ChIP) by streptavidin capture was performed followed by sequencing with a minimum of 50 million reads per sample. After alignment to the genome and peak calling, peaks were characterized and compared to available K562 tracks in the ENCODE database. We found that 45% of identified WT1(+17AA/-KTS) peaks are in the proximity of transcription start sites (promoter area, first exon or first intron) of target genes, whereas only 11% of randomized peaks were found here. Within the peaks we show strong enrichment for three different previously published WT1-binding motifs. Comparison to ENCODE tracks showed that WT1(+17AA/-KTS) peaks are in close proximity to binding sites of other transcription factors, to histone marks for actively transcribed genes, and to binding sites of chromatin modifiers. Considering peaks within promoters and gene bodies only (for safe assignment to a target gene), Gene Ontology (GO) analysis revealed enrichment of GO groups important for proliferation, cell death, embryonic development, and cell motility. In conclusion, WT1(+17AA/-KTS) binds close to transcription start sites in areas of active transcription. The target genes implicated in proliferation, cell death, cell signaling and motility adds to the growing evidence of WT1 as an effector gene in leukemia.
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| 28. |
- von Palffy, Sofia, et al.
(författare)
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A high-content cytokine screen identifies myostatin propeptide as a positive regulator of primitive chronic myeloid leukemia cells
- 2020
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 105:8, s. 2095-2104
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Tidskriftsartikel (refereegranskat)abstract
- Aberrantly expressed cytokines in the bone marrow (BM) niche are increasingly recognized as critical mediators of survival and expansion of leukemic stem cells. To identify regulators of primitive chronic myeloid leukemia (CML) cells, we performed a high-content cytokine screen using primary CD34+ CD38low chronic phase CML cells. Out of the 313 unique human cytokines evaluated, 11 were found to expand cell numbers ≥2-fold in a 7-day culture. Focusing on novel positive regulators of primitive CML cells, the myostatin antagonist myostatin propeptide gave the largest increase in cell expansion and was chosen for further studies. Herein, we demonstrate that myostatin propeptide expands primitive CML and normal BM cells, as shown by increased colony-forming capacity. For primary CML samples, retention of CD34-expression was also seen after culture. Furthermore, we show expression of MSTN by CML mesenchymal stromal cells, and that myostatin propeptide has a direct and instant effect on CML cells, independent of myostatin, by demonstrating binding of myostatin propeptide to the cell surface and increased phosphorylation of STAT5 and SMAD2/3. In summary, we identify myostatin propeptide as a novel positive regulator of primitive CML cells and corresponding normal hematopoietic cells.
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| 29. |
- von Palffy, Sofia, et al.
(författare)
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The complement receptor C3AR constitutes a novel therapeutic target in NPM1-mutated AML
- 2023
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 7:7, s. 1204-1218
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Tidskriftsartikel (refereegranskat)abstract
- Mutated Nucleophosmin 1 (NPM1) is the most common genetic alteration in acute myeloid leukemia (AML), found in approximately 30% of cases. Although mutations in this gene are considered favorable according to current risk stratification guidelines, a large fraction of patients will suffer from relapse, demonstrating the urgent need for new treatment options. Therefore, we aimed to identify cell surface proteins specifically expressed on NPM1)-mutated AML cells, allowing for potential targeting with antibody-based therapies. Herein, we performed an arrayed flow cytometry-based screen directed to 362 cell surface markers. Comparing the cell surface expression on NPM1-mutated AML cells to primitive (CD34+ CD38-) normal bone marrow cells, we identified the complement receptor C3AR as specifically expressed in NPM1-mutated AML. By flow cytometry and single cell RNA-sequencing, we further show that normal hematopoietic stem and progenitor cells lack detectable C3AR gene and protein expression, making it particularly suitable as a target for antibody therapy. We also demonstrate that C3AR in combination with GPR56 distinguishes the leukemic stem cells (LSCs) in NPM1-mutated AML from the normal hematopoietic stem cells, defining the LSC population, as shown by transplantation into immunodeficient mice. Mechanistically, stimulation of C3AR-expressing cells with C3a, the ligand of C3AR, leads to activation of ERK1/2 and increased survival of AML cells, suggesting that this is an important signaling axis in this subtype of AML. Finally, we show that antibodies directed against C3AR efficiently elicit NK cell-mediated killing of primary AML cells ex vivo, highlighting C3AR as a candidate therapeutic target in NPM1-mutated AML.
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| 30. |
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