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181 results on '"Månsson, Robert"'

5. Whole-genome sequencing of chronic lymphocytic leukemia identifies subgroups with distinct biological and clinical features

Author

Robbe, Pauline, Ridout, Kate E., Vavoulis, Dimitrios V., Dréau, Helene, Kinnersley, Ben, Denny, Nicholas, Chubb, Daniel, Appleby, Niamh, Cutts, Anthony, Cornish, Alex J., Lopez-Pascua, Laura, Clifford, Ruth, Burns, Adam, Stamatopoulos, Basile, Cabes, Maite, Alsolami, Reem, Antoniou, Pavlos, Oates, Melanie, Cavalieri, Doriane, Gibson, Jane, Prabhu, Anika V., Schwessinger, Ron, Jennings, Daisy, James, Terena, Maheswari, Uma, Duran-Ferrer, Martí, Carninci, Piero, Knight, Samantha J. L., Månsson, Robert, Hughes, Jim, Davies, James, Ross, Mark, Bentley, David, Strefford, Jonathan C., Devereux, Stephen, Pettitt, Andrew R., Hillmen, Peter, Caulfield, Mark J., Houlston, Richard S., Martín-Subero, José I., and Schuh, Anna

Published
2022
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9. Limited access to antigen drives generation of early B cell memory while restraining the plasmablast response

Author

Glaros, Vassilis, Rauschmeier, René, Artemov, Artem V., Reinhardt, Annika, Ols, Sebastian, Emmanouilidi, Aikaterini, Gustafsson, Charlotte, You, Yuanyuan, Mirabello, Claudio, Björklund, Åsa K., Perez, Laurent, King, Neil P., Månsson, Robert, Angeletti, Davide, Loré, Karin, Adameyko, Igor, Busslinger, Meinrad, and Kreslavsky, Taras

Published
2021
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22. FOXO1 and FOXO3 Cooperatively Regulate Innate Lymphoid Cell Development

Author

Luu, Thuy T., Søndergaard, Jonas Nørskov, Peña-Pérez, Lucía, Kharazi, Shabnam, Krstic, Aleksandra, Meinke, Stephan, Schmied, Laurent, Frengen, Nicolai, Heshmati, Yaser, Kierczak, Marcin, Bouderlique, Thibault, Wagner, Arnika Kathleen, Gustafsson, Charlotte, Chambers, Benedict J., Achour, Adnane, Kutter, Claudia, Höglund, Petter, Månsson, Robert, and Kadri, Nadir

Subjects
natural killer cells, IL-15, innate lymphocyte cells (ILCs), Immunologi inom det medicinska området, Immunology, Immunology and Allergy, Immunology in the medical area, FOXO, Utvecklingsbiologi, development, Developmental Biology
Abstract

Natural killer (NK) cells play roles in viral clearance and early surveillance against malignant transformation, yet our knowledge of the underlying mechanisms controlling their development and functions remain incomplete. To reveal cell fate-determining pathways in NK cell progenitors (NKP), we utilized an unbiased approach and generated comprehensive gene expression profiles of NK cell progenitors. We found that the NK cell program was gradually established in the CLP to preNKP and preNKP to rNKP transitions. In line with FOXO1 and FOXO3 being co-expressed through the NK developmental trajectory, the loss of both perturbed the establishment of the NK cell program and caused stalling in both NK cell development and maturation. In addition, we found that the combined loss of FOXO1 and FOXO3 caused specific changes to the composition of the non-cytotoxic innate lymphoid cell (ILC) subsets in bone marrow, spleen, and thymus. By combining transcriptome and chromatin profiling, we revealed that FOXO TFs ensure proper NK cell development at various lineage-commitment stages through orchestrating distinct molecular mechanisms. Combined FOXO1 and FOXO3 deficiency in common and innate lymphoid cell progenitors resulted in reduced expression of genes associated with NK cell development including ETS-1 and their downstream target genes. Lastly, we found that FOXO1 and FOXO3 controlled the survival of committed NK cells via gene regulation of IL-15R beta (CD122) on rNKPs and bone marrow NK cells. Overall, we revealed that FOXO1 and FOXO3 function in a coordinated manner to regulate essential developmental genes at multiple stages during murine NK cell and ILC lineage commitment.

Published
2022

32. Splice-correcting oligonucleotides restore BTK function in X-linked agammaglobulinemia model

Author

Bestas, Burcu, Moreno, Pedro M.D., Blomberg, Emelie K. M., Mohammad, Dara K., Saleh, Amer F., Sutlu, Tolga, Nordin, Joel Z., Guterstam, Peter, Gustafsson, Manuela O., Kharazi, Shabnam, Piątosa, Barbara, Roberts, Thomas C., Behlke, Mark A., Wood, Matthew J.A., Gait, Michael J., Lundin, Karin E., El Andaloussi, Samir, Månsson, Robert, Berglöf, Anna, Wengel, Jesper, and Smith, Edvard C.I.

Published
2014
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39. FOXO Dictates Initiation of B Cell Development and Myeloid Restriction in Common Lymphoid Progenitors.

Author

Peña-Pérez, Lucía, Kharazi, Shabnam, Frengen, Nicolai, Krstic, Aleksandra, Bouderlique, Thibault, Hauenstein, Julia, He, Minghui, Somuncular, Ece, Li Wang, Xiaoze, Dahlberg, Carin, Gustafsson, Charlotte, Johansson, Ann-Sofie, Walfridsson, Julian, Kadri, Nadir, Woll, Petter, Kierczak, Marcin, Qian, Hong, Westerberg, Lisa, Luc, Sidinh, and Månsson, Robert

Subjects
B cells, MYELOID cells, CELL determination, REGULATOR genes, FORKHEAD transcription factors
Abstract

The development of B cells relies on an intricate network of transcription factors critical for developmental progression and lineage commitment. In the B cell developmental trajectory, a temporal switch from predominant Foxo3 to Foxo1 expression occurs at the CLP stage. Utilizing VAV-iCre mediated conditional deletion, we found that the loss of FOXO3 impaired B cell development from LMPP down to B cell precursors, while the loss of FOXO1 impaired B cell commitment and resulted in a complete developmental block at the CD25 negative proB cell stage. Strikingly, the combined loss of FOXO1 and FOXO3 resulted in the failure to restrict the myeloid potential of CLPs and the complete loss of the B cell lineage. This is underpinned by the failure to enforce the early B-lineage gene regulatory circuitry upon a predominantly pre-established open chromatin landscape. Altogether, this demonstrates that FOXO3 and FOXO1 cooperatively govern early lineage restriction and initiation of B-lineage commitment in CLPs. [ABSTRACT FROM AUTHOR]

Published
2022
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44. Genomics based analysis of interactions between developing B-lymphocytes and stromal cells reveal complex interactions and two-way communication

Author

Bryder David, Hansson Frida, Lagergren Anna, Månsson Robert, Zandi Sasan, Qian Hong, Zetterblad Jenny, Paulsson Nils, and Sigvardsson Mikael

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background The use of functional genomics has largely increased our understanding of cell biology and promises to help the development of systems biology needed to understand the complex order of events that regulates cellular differentiation in vivo. One model system clearly dependent on the integration of extra and intra cellular signals is the development of B-lymphocytes from hematopoietic stem cells in the bone marrow. This developmental pathway involves several defined differentiation stages associated with specific expression of genes including surface markers that can be used for the prospective isolation of the progenitor cells directly from the bone marrow to allow for ex vivo gene expression analysis. The developmental process can be simulated in vitro making it possible to dissect information about cell/cell communication as well as to address the relevance of communication pathways in a rather direct manner. Thus we believe that B-lymphocyte development represents a useful model system to take the first steps towards systems biology investigations in the bone marrow. Results In order to identify extra cellular signals that promote B lymphocyte development we created a database with approximately 400 receptor ligand pairs and software matching gene expression data from two cell populations to obtain information about possible communication pathways. Using this database and gene expression data from NIH3T3 cells (unable to support B cell development), OP-9 cells (strongly supportive of B cell development), pro-B and pre-B cells as well as mature peripheral B-lineage cells, we were able to identify a set of potential stage and stromal cell restricted communication pathways. Functional analysis of some of these potential ways of communication allowed us to identify BMP-4 as a potent stimulator of B-cell development in vitro. Further, the analysis suggested that there existed possibilities for progenitor B cells to send signals to the stroma. The functional consequences of this were investigated by co-culture experiments revealing that the co-incubation of stromal cells with B cell progenitors altered both the morphology and the gene expression pattern in the stromal cells. Conclusions We believe that this gene expression data analysis method allows for the identification of functionally relevant interactions and therefore could be applied to other data sets to unravel novel communication pathways.

Published
2010
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45. Exit of pediatric pre-B acute lymphoblastic leukaemia cells from the bone marrow to the peripheral blood is not associated with cell maturation or alterations in gene expression

Author

Wiebe Thomas, Jacobsen Sten, Norén-Nyström Ulrika, Johansson Bertil, Månsson Robert, Toporski Jacek, Hansson Frida, Larsson Marcus, Sigvardsson Mikael, and Castor Anders

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Childhood pre-B acute lymphoblastic leukemia (ALL) is a bone marrow (BM) derived disease, which often disseminates out of the BM cavity, where malignant cells to a variable degree can be found circulating in the peripheral blood (PB). Normal pre-B cells are absolutely dependent on BM stroma for survival and differentiation. It is not known whether transformed pre-B ALL cells retain any of this dependence, which possibly could impact on drug sensitivity or MRD measurements. Results Pre-B ALL cells, highly purified by a novel method using surface expression of CD19 and immunoglobulin light chains, from BM and PB show a very high degree of similarity in gene expression patterns, with differential expression of vascular endothelial growth factor (VEGF) as a notable exception. In addition, the cell sorting procedure revealed that in 2 out of five investigated patients, a significant fraction of the malignant cells had matured beyond the pre-B cell stage. Conclusion The transition of ALL cells from the BM into the circulation does not demand, or result in, major changes of gene expression pattern. This might indicate an independence of BM stroma on the part of transformed pre-B cells, which contrasts with that of their normal counterparts.

Published
2008
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46. The transcription factor Bcl11b promotes both canonical and adaptive NK cell differentiation.

Author

Holmes, Tim D., Pandey, Ram Vinay, Helm, Eric Y., Schlums, Heinrich, Han, Hongya, Campbell, Tessa M., Drashansky, Theodore T., Chiang, Samuel, Wu, Cheng-Ying, Tao, Christine, Shoukier, Moneef, Tolosa, Eva, Von Hardenberg, Sandra, Sun, Miao, Klemann, Christian, Marsh, Rebecca A., Lau, Colleen M., Lin, Yin, Sun, Joseph C., and Månsson, Robert

Abstract

Human NK cell circuitry: Natural killer (NK) cells are innate immune effector cells that undergo differentiation and education to facilitate protective responses during viral infection and cancer. Holmes et al. performed an integrated transcriptional and epigenetic profiling of human peripheral blood NK cell subsets to construct the transcription factor networks regulating their differentiation. NK cell differentiation converged along an axis that terminated in adaptive NK cells and was progressively regulated by the transcription factor Bcl11b. Ectopic expression of Bcl11b or loss of function in patients harboring BCL11B mutations altered NK cell maturation. Although Bcl11b is known to regulate T cell development, these results identify a complementary role in NK cell differentiation and provide insight into other transcription factors potentially involved in human NK cell identity. See related Focus by Rückert et al. in this issue. Epigenetic landscapes can provide insight into regulation of gene expression and cellular diversity. Here, we examined the transcriptional and epigenetic profiles of seven human blood natural killer (NK) cell populations, including adaptive NK cells. The BCL11B gene, encoding a transcription factor (TF) essential for T cell development and function, was the most extensively regulated, with expression increasing throughout NK cell differentiation. Several Bcl11b-regulated genes associated with T cell signaling were specifically expressed in adaptive NK cell subsets. Regulatory networks revealed reciprocal regulation at distinct stages of NK cell differentiation, with Bcl11b repressing RUNX2 and ZBTB16 in canonical and adaptive NK cells, respectively. A critical role for Bcl11b in driving NK cell differentiation was corroborated in BCL11B-mutated patients and by ectopic Bcl11b expression. Moreover, Bcl11b was required for adaptive NK cell responses in a murine cytomegalovirus model, supporting expansion of these cells. Together, we define the TF regulatory circuitry of human NK cells and uncover a critical role for Bcl11b in promoting NK cell differentiation and function. [ABSTRACT FROM AUTHOR]

Published
2021
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47. Predictive screening for regulators of conserved functional gene modules (gene batteries) in mammals

Author

Sigvardsson Mikael, Nerman Olle, Månsson Robert, Kristiansson Erik, Larsson Erik, Nelander Sven, Mostad Petter, and Lindahl Per

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background The expression of gene batteries, genomic units of functionally linked genes which are activated by similar sets of cis- and trans-acting regulators, has been proposed as a major determinant of cell specialization in metazoans. We developed a predictive procedure to screen the mouse and human genomes and transcriptomes for cases of gene-battery-like regulation. Results In a screen that covered ~40 per cent of all annotated protein-coding genes, we identified 21 co-expressed gene clusters with statistically supported sharing of cis-regulatory sequence elements. 66 predicted cases of over-represented transcription factor binding motifs were validated against the literature and fell into three categories: (i) previously described cases of gene battery-like regulation, (ii) previously unreported cases of gene battery-like regulation with some support in a limited number of genes, and (iii) predicted cases that currently lack experimental support. The novel predictions include for example Sox 17 and RFX transcription factor binding sites that were detected in ~10% of all testis specific genes, and HNF-1 and 4 binding sites that were detected in ~30% of all kidney specific genes respectively. The results are publicly available at http://www.wlab.gu.se/lindahl/genebatteries. Conclusion 21 co-expressed gene clusters were enriched for a total of 66 shared cis-regulatory sequence elements. A majority of these predictions represent novel cases of potential co-regulation of functionally coupled proteins. Critical technical parameters were evaluated, and the results and the methods provide a valuable resource for future experimental design.

Published
2005
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49. Mice deficient of Myc super-enhancer region reveal a differential control mechanism between normal and pathological growth

Author

Dave, Kashyap, Sur, Inderpreet, Yan, Jian, Zhang, Jilin, Kaasinen, Eevi, Zhong, Fan, Blaas, Leander, Li, Xiaoze, Månsson, Robert, and Taipale, Jussi

Abstract

The gene desert upstream of the Myc oncogene on chromosome 8q24 contains susceptibility loci for several major forms of human cancer, including cancers of breast, prostate, and colon. The region shows high conservation between human and mouse and contains multiple MYC enhancers that are activated in tumor cells. However, the role of this region in normal development has not been addressed. Here we show that a 538 kb deletion of the entire MYC upstream super-enhancer region in mice results in 50 to 80% decrease in MYC expression in multiple tissues. The mice are viable and show no overt phenotype. However, they are resistant to tumorigenesis, and most normal cells isolated from them grow slowly in culture. Consistently, deletion of the 8q24 super-enhancer region perturbs Myc targets only in cultured cells, but not in vivo . These results reveal that only cells whose Myc activity is increased by serum or oncogenic driver mutations depend on the 8q24 super-enhancer region, and indicate that targeting the activity of this element is a promising strategy of cancer chemoprevention and therapy.

Published
2016
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50. Upfront bortezomib, lenalidomide, and dexamethasone compared to bortezomib, cyclophosphamide, and dexamethasone in multiple myeloma.

Author

Uttervall, Katarina, Borg Bruchfeld, Johanna, Gran, Charlotte, Wålinder, Göran, Månsson, Robert, Lund, Johan, Gahrton, Gösta, Alici, Evren, and Nahi, Hareth

Subjects
MULTIPLE myeloma, STEM cell transplantation, BORTEZOMIB, DEXAMETHASONE, PROGRESSION-free survival
Abstract

Objectives: At our center, patients with multiple myeloma (MM) were treated upfront with bortezomib, cyclophosphamide, and dexamethasone (VCD) until cyclophosphamide was replaced with lenalidomide in the combination (VRD). These treatments have never been compared head‐to‐head in large real‐life patient material. Method: A retrospective analysis of patients treated with VRD and VCD in the first line, both with and without subsequent high‐dose treatment (HDT) and autologous stem cell transplantation. A total of 681 patients were included, 117 receiving VRD (71 with, 46 without HDT) and 564 receiving VCD (351 with, 213 without HDT). Results: Overall response rate (≥partial response) was higher with VRD compared to VCD in the entire VRD group (98% vs 88%, P < 0.001) and in the non‐HDT group (98% vs 79%, P < 0.001). Progression‐free survival (PFS) at 18 months was longer with VRD compared to VCD in the entire VRD group, the non‐HDT group and the HDT group (88% vs 63%, 82% vs 32% and 91% vs 73%, respectively). Overall survival at 18 months was better for VRD‐treated patients in the entire VRD group (95% vs 89%, P = 0.048). Conclusion: Upfront VRD gives better responses and longer PFS compared to VCD in MM patients with or without subsequent HDT. [ABSTRACT FROM AUTHOR]

Published
2019
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