| 1. |
- C. Lin, Yin, et al.
(author)
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A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate
- 2010
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In: Nature Immunology. - : Nature Publishing Group. - 1529-2908 .- 1529-2916. ; 11:7, s. 635-U109
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Journal article (peer-reviewed)abstract
- It is now established that the transcription factors E2A, EBF1 and Foxo1 have critical roles in B cell development. Here we show that E2A and EBF1 bound regulatory elements present in the Foxo1 locus. E2A and EBF1, as well as E2A and Foxo1, in turn, were wired together by a vast spectrum of cis-regulatory sequences. These associations were dynamic during developmental progression. Occupancy by the E2A isoform E47 directly resulted in greater abundance, as well as a pattern of monomethylation of histone H3 at lysine 4 (H3K4) across putative enhancer regions. Finally, we divided the pro-B cell epigenome into clusters of loci with occupancy by E2A, EBF and Foxo1. From this analysis we constructed a global network consisting of transcriptional regulators, signaling and survival factors that we propose orchestrates B cell fate.
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| 2. |
- Ekblad, Lars, et al.
(author)
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Anti- or pro-proliferation - Conditional options for TGF-α and cetuximab in head and neck squamous cell carcinoma.
- 2015
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In: Oral Oncology. - : Elsevier BV. - 1879-0593 .- 1368-8375. ; 51:1, s. 46-52
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Journal article (peer-reviewed)abstract
- Cetuximab is an epidermal growth factor receptor (EGFR)-targeting drug that has shown effects in head and neck squamous cell carcinoma (HNSCC). The effects are, however, small and have mainly been proven in a subset of patients, and the cost-effectiveness has been questioned. For this reason, we need to know more about the basic mechanisms controlling the effect of EGFR signalling on tumour growth.
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| 3. |
- Indira Chandran, Vineesh, et al.
(author)
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Ultrasensitive Immunoprofiling of Plasma Extracellular Vesicles Identifies Syndecan-1 as a Potential Tool for Minimally Invasive Diagnosis of Glioma
- 2019
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In: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 25:10, s. 3115-3127
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Journal article (peer-reviewed)abstract
- Purpose: Liquid biopsy has great potential to improve the management of brain tumor patients at high risk of surgery-associated complications. Here, the aim was to explore plasma extracellular vesicle (plEV) immunoprofiling as a tool for noninvasive diagnosis of glioma.Experimental Design: PlEV isolation and analysis were optimized using advanced mass spectrometry, nanoparticle tracking analysis, and electron microscopy. We then established a new procedure that combines size exclusion chromatography isolation and proximity extension assay-based ultrasensitive immunoprofiling of plEV proteins that was applied on a well-defined glioma study cohort (n = 82).Results: Among potential candidates, we for the first time identify syndecan-1 (SDC1) as a plEV constituent that can discriminate between high-grade glioblastoma multiforme (GBM, WHO grade IV) and low-grade glioma [LGG, WHO grade II; area under the ROC curve (AUC): 0.81; sensitivity: 71%; specificity: 91%]. These findings were independently validated by ELISA. Tumor SDC1 mRNA expression similarly discriminated between GBM and LGG in an independent glioma patient population from The Cancer Genome Atlas cohort (AUC: 0.91; sensitivity: 79%; specificity: 91%). In experimental studies with GBM cells, we show that SDC1 is efficiently sorted to secreted EVs. Importantly, we found strong support of plEVSDC1 originating from GBM tumors, as plEVSDC1 correlated with SDC1 protein expression in matched patient tumors, and plEVSDC1 was decreased postoperatively depending on the extent of surgery.Conclusions: Our studies support the concept of circulating plEVs as a tool for noninvasive diagnosis and monitoring of gliomas and should move this field closer to the goal of improving the management of cancer patients.
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| 4. |
- Källberg, Eva, et al.
(author)
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AIRE is expressed in breast cancer TANs and TAMs to regulate the extrinsic apoptotic pathway and inflammation
- 2024
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In: Journal of Leukocyte Biology. - 1938-3673. ; 115:4, s. 664-678
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Journal article (peer-reviewed)abstract
- Autoimmune regulator (AIRE) is a transcriptional regulator expressed in the thymus and necessary for maintaining immunological self-tolerance. Extra-thymic AIRE expression is rare and a role for AIRE in tumor-associated innate immune cells has not yet been established. In this study we show that AIRE is expressed in human pro-tumor neutrophils. In breast cancer, AIRE was primarily located to tumor associated neutrophils (TANs), and to a lesser extent to tumor associated macrophages (TAMs) and tumor cells. Expression of AIRE in TAN/TAMs, but not in cancer cells, was associated with an adverse prognosis. We show that the functional role for AIRE in neutrophils and macrophages is to regulate expression of immune mediators and the extrinsic apoptotic pathway involving the Fas/TNFR death receptors and Cathepsin G. We here propose that the role for AIRE in TAN/TAMs in breast tumors is to regulate cell death and inflammation, thus promoting tumor progression.
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| 5. |
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| 6. |
- Mansson, Robert, et al.
(author)
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Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate
- 2012
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In: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 109:51, s. 21028-21033
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Journal article (peer-reviewed)abstract
- Recent studies have identified a number of transcriptional regulators, including E2A, early B-cell factor 1 (EBF1), FOXO1, and paired box gene 5 (PAX5), that promote early B-cell development. However, how this ensemble of regulators mechanistically promotes B-cell fate remains poorly understood. Here we demonstrate that B-cell development in FOXO1-deficient mice is arrested in the common lymphoid progenitor (CLP) LY6D(+) cell stage. We demonstrate that this phenotype closely resembles the arrest in B-cell development observed in EBF1-deficient mice. Consistent with these observations, we find that the transcription signatures of FOXO1- and EBF1-deficient LY6D(+) progenitors are strikingly similar, indicating a common set of target genes. Furthermore, we found that depletion of EBF1 expression in LY6D(+) CLPs severely affects FOXO1 mRNA abundance, whereas depletion of FOXO1 activity in LY6D(+) CLPs ablates EBF1 transcript levels. We generated a global regulatory network from EBF1 and FOXO1 genome-wide transcription factor occupancy and transcription signatures derived from EBF1- and FOXO1-deficient CLPs. This analysis reveals that EBF1 and FOXO1 act in a positive feedback circuitry to promote and stabilize specification to the B-cell lineage.
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| 7. |
- Menard, Julien A., et al.
(author)
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Metastasis Stimulation by Hypoxia and Acidosis-Induced Extracellular Lipid Uptake Is Mediated by Proteoglycan-Dependent Endocytosis
- 2016
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In: Cancer Research. - 0008-5472 .- 1538-7445. ; 76:16, s. 4828-4840
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Journal article (peer-reviewed)abstract
- Hypoxia and acidosis are inherent stress factors of the tumor microenvironment and have been linked to increased tumor aggressiveness and treatment resistance. Molecules involved in the adaptive mechanisms that drive stress-induced disease progression constitute interesting candidates of therapeutic intervention. Here, we provide evidence of a novel role of heparan sulfate proteoglycans (HSPG) in the adaptive response of tumor cells to hypoxia and acidosis through increased internalization of lipoproteins, resulting in a lipid-storing phenotype and enhanced tumor-forming capacity. Patient glioblastoma tumors and cells under hypoxic and acidic stress acquired a lipid droplet (LD)-loaded phenotype, and showed an increased recruitment of all major lipoproteins, HDL, LDL, and VLDL. Stress-induced LD accumulation was associated with increased spheroid-forming capacity during reoxygenation in vitro and lung metastatic potential in vivo. On a mechanistic level, we found no apparent effect of hypoxia on HSPGs, whereas lipoprotein receptors (VLDLR and SR-B1) were transiently upregulated by hypoxia. Importantly, however, using pharmacologic and genetic approaches, we show that stress-mediated lipoprotein uptake is highly dependent on intact HSPG expression. The functional relevance of HSPG in the context of tumor cell stress was evidenced by HSPG-dependent lipoprotein cell signaling activation through the ERK/MAPK pathway and by reversal of the LD-loaded phenotype by targeting of HSPGs. We conclude that HSPGs may have an important role in the adaptive response to major stress factors of the tumor microenvironment, with functional consequences on tumor cell signaling and metastatic potential.
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| 8. |
- Månsson, Robert, et al.
(author)
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Single-cell analysis of the common lymphoid progenitor compartment reveals functional and molecular heterogeneity
- 2010
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 115:13, s. 2601-2609
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Journal article (peer-reviewed)abstract
- To investigate molecular events involved in the regulation of lymphoid lineage commitment, we crossed lambda 5 reporter transgenic mice to Rag1-GFP knockin mice. This allowed us to subfractionate common lymphoid progenitors and pre-pro-B (fraction A) cells into lambda 5(-)Rag1(low), lambda 5(-)Rag1(high), and lambda 5(+)Rag1(high) cells. Clonal in vitro differentiation analysis demonstrated that Rag1(low) cells gave rise to B/T and NK cells. Rag1(high) cells displayed reduced NK-cell potential with preserved capacity to generate B- and T-lineage cells, whereas the lambda 5(+) cells were B-lineage restricted. Ebf1 and Pax5 expression was largely confined to the Rag1high populations. These cells also expressed a higher level of the surface protein LY6D, providing an additional tool for the analysis of early lymphoid development. These data suggest that the classic common lymphoid progenitor compartment composes a mixture of cells with relatively restricted lineage potentials, thus opening new possibilities to investigate early hematopoiesis.
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| 9. |
- Skovbjerg, Susann, 1973, et al.
(author)
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Optimization of the detection of microbes in blood from immunocompromised patients with haematological malignancies.
- 2009
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In: Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. - : Elsevier BV. - 1469-0691. ; 15:7, s. 680-3
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Journal article (peer-reviewed)abstract
- The present study aimed to improve the rate of detection of blood-borne microbes by using PCRs with pan-bacterial and Candida specificity. Seventeen per cent of the blood samples (n=178) collected from 107 febrile patients with haematological malignancies were positive using standard culture (BacT/Alert system). Candida PCR was positive in 12 patients, only one of whom scored culture-positive. Bacterial PCR using fresh blood samples was often negative, but the detection rate increased when the blood was pre-incubated for 2 days. These data indicate that PCR assays might be a complement for the detection of blood-borne opportunists in immunocompromised haematology patients.
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| 10. |
- Tsapogas, Panagiotis, et al.
(author)
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Functional and molecular analysis of B-lineage commitment suggests an instructive role for Il-7 in the earliest lymphoid restricted cells
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Other publication (other academic/artistic)abstract
- Deficiencies in the Il-7 signaling pathway result in severe disruptions of lymphoid development in adult mice. In order to understand how Il-7 deficiency impacts early lymphoid development we have investigated lineage restriction events within the CLP compartment of Il-7 knock out mice. This revealed that while Il-7 deficiency had a minor impact on the development and functional properties of LY6D- multipotent CLPs, the formation of the lineage restricted LY6D+ CLP population was dramatically reduced. This was reflected in a low level transcription of B-lineage genes as well as in a loss of functional B-cell commitment in developing progenitors. The defect could not be rescued by ectopic expression of Bcl-2 suggesting that the cytokine act in an instructive manner in early lymphoid development. This clarifies the role of Il-7 in early lymphoid development and puts emphasis on the relevance of the recently defined lineage restricted progenitor cells in lymphoid differentiation.
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| 11. |
- Tsapogas, Panagiotis, et al.
(author)
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IL-7 mediates Ebf-1-dependent lineage restriction in early lymphoid progenitors
- 2011
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In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 118:5, s. 1283-1290
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Journal article (peer-reviewed)abstract
- eficiencies in the IL-7 signaling pathway result in severe disruptions of lymphoid development in adult mice. To understand more about how IL-7 deficiency impacts early lymphoid development, we have investigated lineage restriction events within the common lymphoid progenitor (CLP) compartment in IL-7 knockout mice. This revealed that although IL-7 deficiency had a minor impact on the development of LY6D(-) multipotent CLPs, the formation of the lineage restricted LY6D(+) CLP population was dramatically reduced. This was reflected in a low-level transcription of B-lineage genes as well as in a loss of functional B-cell commitment. The few Ly6D(+) CLPs developed in the absence of IL-7 displayed increased lineage plasticity and low expression of Ebf-1. Absence of Ebf-1 could be linked to increased plasticity because even though Ly6D(+) cells develop in Ebf-1-deficient mice, these cells retain both natural killer and dendritic cell potential. This reveals that IL-7 is essential for normal development of Ly6D(+) CLPs and that Ebf-1 is crucial for lineage restriction in early lymphoid progenitors.
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| 12. |
- Welinder, Eva, et al.
(author)
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B-lymphocyte commitment : Identifying the point of no return
- 2011
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In: Seminars in Immunology. - : Elsevier. - 1044-5323 .- 1096-3618. ; 23:5, s. 335-340
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Research review (peer-reviewed)abstract
- Even though B-lymphocyte development is one of the best understood models for cell differentiation in the hematopoetic system, recent advances in cell sorting and functional genomics has increased this understanding further. This has suggested that already early lymphoid primed multipotent progenitor cells (LMPPs) express low levels of lymphoid restricted transcripts. The expression of these genes becomes more pronounced when cells enter the FLT-3/IL-7 receptor positive common lymphoid progenitor (CLP) stage. However, the expression of B-lineage specific genes is limited to a B-cell restricted Ly6D surface positive subpopulation of the CLP compartment. The gene expression patterns also reflect differences in lineage potential and while Ly6D negative FLT-3/IL-7 receptor positive cells represents true CLPs with an ability to generate B/T and NK cells, the Ly6D positive cells lack NK cell potential and display a reduced T-cell potential in vivo. These recent findings suggest that the CLP compartment is highly heterogenous and that the point of no return in B-cell development may occur already in B220(-) CD19(-) cells. These findings have allowed for a better understanding of the interplay between transcription factors like EBF-1, PAX-5 and E47, all known as crucial for normal B-cell development. In this review, we aim to provide a comprehensive overview of B-cell fate specification and commitment based on the recent advances in the understanding of molecular networks as well as functional properties of early progenitor populations. (C) 2011 Elsevier Ltd. All rights reserved.
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| 13. |
- Welinder, Eva
(author)
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ELUCIDATING REGULATORY NETWORKS PROMOTING B-CELL DEVELOPMENT
- 2012
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Doctoral thesis (other academic/artistic)abstract
- B-cells are an essential part of our adaptive immune system. A network of transcription factors together with external signals facilitate the gradual developmental progression from progenitor cells towards the B-cell fate. Several key factors participating in this network have been identified. Among these are the transcription factors E2A, HEB, EBF1 and FOXO1 as well as the IL7 signaling cascade. The objective of this thesis has been to increase our understanding of the transcriptional network orchestrating B-lineage specification and commitment. Based on the combined expression of surface markers and transgenic reporter genes, we have identified three hierarchically related and functionally distinct subpopulations within the common lymphoid progenitor (CLP) compartment. Using this knowledge, we have re-evaluated previously characterized knock-out mouse models in order to obtain a higher resolution analysis of critical events in early B-cell commitment. Based on these studies, we propose a transcriptional hierarchy where the transcription factors E2A and HEB initiate the B-cell specification program in the LY6D- CLPs through up regulation of FOXO1. During the transition to LY6D expressing CLPs, E2A and FOXO1 induce EBF1. Subsequently, FOXO1 and EBF1 generate a feed-forward loop, leading to activation of PAX5, B-cell commitment and the progression to the CD19+ pro-B cell stage.
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| 14. |
- Welinder, Eva, et al.
(author)
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The transcription factors E2A and HEB act in concert to induce the expression of FOXO1 in the common lymphoid progenitor
- 2011
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In: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:42, s. 17402-17407
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Journal article (peer-reviewed)abstract
- Recent studies have identified a number of transcriptional regulators, including E proteins, EBF1, FOXO1, and PAX5, that act together to orchestrate the B-cell fate. However, it still remains unclear as to how they are linked at the earliest stages of B-cell development. Here, we show that lymphocyte development in HEB-ablated mice exhibits a partial developmental arrest, whereas B-cell development in E2A(+/-)HEB(-/)-mice is completely blocked at the LY6D(-) common lymphoid progenitor stage. We show that the transcription signatures of E2A-and HEB-ablated common lymphoid progenitors significantly overlap. Notably, we found that Foxo1 expression was substantially reduced in the LY6D-HEB-and E2A-deficient cells. Finally, we show that E2A binds to enhancer elements across the FOXO1 locus to activate Foxo1 expression, linking E2A and FOXO1 directly in a common pathway. In summary, the data indicate that the earliest event in B-cell specification involves the induction of FOXO1 expression and requires the combined activities of E2A and HEB.
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| 15. |
- Welinder-Olsson, Christina, 1959, et al.
(author)
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EHEC outbreak among staff at a children's hospital--use of PCR for verocytotoxin detection and PFGE for epidemiological investigation.
- 2004
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In: Epidemiology and infection. - 0950-2688. ; 132:1, s. 43-9
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Journal article (peer-reviewed)abstract
- This is the first report of a major foodborne outbreak of enterohaemorrhagic Escherichia coli (EHEC) in Sweden. It occurred among the nursing staff at a children's hospital with approximately 1600 employees. Contaminated lettuce was the most likely source of infection. Nine persons were culture-positive for Escherichia coli (E. coli) O157 and verocytotoxin-positive by PCR and a further two were verocytotoxin-positive by PCR only. All 11 EHEC-positive individuals had attended a party for approximately 250 staff members, which was held at the hospital. In a questionnaire 37 persons stated that they had symptoms consistent with EHEC infection during the weeks after the party. There was no evidence of secondary transmission from staff to patients. The value of PCR as a sensitive and fast method for diagnosis is discussed in this paper. Pulsed-field gel electrophoresis (PFGE) was used to ascertain that staff members were infected by the same clone, and that two patients with E. coli O157 infection were not.
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| 16. |
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| 17. |
- Welinder-Olsson, Christina, 1959, et al.
(author)
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Genetic profiling of enterohemorrhagic Escherichia coli strains in relation to clonality and clinical signs of infection.
- 2002
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In: Journal of clinical microbiology. - 0095-1137. ; 40:3, s. 959-64
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Journal article (peer-reviewed)abstract
- Sixty-seven human strains of enterohemorrhagic Escherichia coli (EHEC) (from patients with more or less severe symptoms) were serogrouped and arranged according to pulsed-field gel electrophoresis (PFGE) patterns. We used PCR to investigate the strains according to known or putative virulence factors, and associations with disease were studied. All EHEC strains with the same PFGE pattern belonged to the same serogroup. On the contrary, two serogroups (O157 and O8) included strains with different PFGE patterns. We found several different combinations of chromosomal and plasmid-borne determinants, encoding the putative virulence factors, among the strains. As judged from clinical symptoms, there was no marked difference in pathogenicity among the strains and their combinations of virulence traits. All strains of O157 had the genes coding for verocytotoxin (VT) 2, intimin (eaeA), E. coli hemolysin (E-hly), and secreted serine protease (espP). Among EHEC non-O157 strains, the genes coding for VT1 and VT2 were equally dispersed. EaeA positivity was just as common among VT1- as VT2-positive strains. Among the plasmid-borne determinants, E-hly and espP were the most common and E-hly might be a pathogenicity marker among EHEC non-O157 strains. The conclusion is that PFGE is a very useful tool in epidemiological studies. The EHEC plasmids are heterogeneous in their gene composition, with the four plasmid-borne determinants found in many combinations. There was no reliable correlation between chromosomal and plasmid-borne virulence factors and human disease.
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| 18. |
- Welinder-Olsson, Christina, 1959, et al.
(author)
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Improved microbiological techniques using the polymerase chain reaction and pulsed-field gel electrophoresis for diagnosis and follow-up of enterohaemorrhagic Escherichia coli infection.
- 2000
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In: European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. - 0934-9723. ; 19:11, s. 843-51
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Journal article (peer-reviewed)abstract
- The aims of the present investigation were to evaluate the microbiological diagnostic procedures, especially polymerase chain reaction (PCR) versus culture and seroagglutination, in relation to the clinical features of enterohaemorrhagic Escherichia coli (EHEC) infection and to study the status of EHEC in the western part of Sweden. During 1997 and 1998, stool specimens from 3,948 patients were analysed by PCR for the presence of EHEC with verotoxin (VT)1- and/or VT2-producing DNA sequences. The stool specimens were also cultured for Escherichia coli O157:H7, Salmonella, Campylobacter, Shigella and Yersinia. Fifty-five patients were positive by PCR. Thirty-nine patients were positive for EHEC by PCR and culture. Of these, 29 were infected with EHEC serogroup O157:H7 strains. All EHEC isolates were analysed by pulsed-field gel electrophoresis (PFGE); 17 different clones were identified. Studies on the duration of the presence of EHEC in the gut showed that EHEC often disappears rather quickly, i.e. within 2 weeks. In one patient, however, EHEC remained for several months. In conclusion, PCR, rather than culture and agglutination, should be the method of choice for microbiological diagnosis of EHEC infection. PCR is more sensitive than culture for detecting EHEC in the gut.
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| 19. |
- Wendel, Ulrika, et al.
(author)
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A novel monoclonal antibody targeting carboxymethyllysine, an advanced glycation end product in atherosclerosis and pancreatic cancer
- 2018
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:2
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Journal article (peer-reviewed)abstract
- Advanced glycation end products are formed by non-enzymatic reactions between proteins and carbohydrates, causing irreversible lysine and arginine alterations that severely affect protein structure and function. The resulting modifications induce inflammation by binding to scavenger receptors. An increase in advanced glycation end products is observed in a number of diseases e.g. atherosclerosis and cancer. Since advanced glycation end products also are present in healthy individuals, their detection and quantification are of great importance for usage as potential biomarkers. Current methods for advanced glycation end product detection are though limited and solely measure total glycation. This study describes a new epitope-mapped single chain variable fragment, D1-B2, against carboxymethyllysine, produced from a phage library that was constructed from mouse immunizations. The phage library was selected against advanced glycation end product targets using a phage display platform. Characterization of its binding pattern was performed using large synthetic glycated peptide and protein libraries displayed on microarray slides. D1-B2 showed a preference for an aspartic acid, three positions N-terminally from a carboxymethyllysine residue and also bound to a broad collection of glycated proteins. Positive immunohistochemical staining of mouse atherosclerotic plaques and of a tissue microarray of human pancreatic tumors confirmed the usability of the new scFv for advanced glycation end product detection in tissues. This study demonstrates a promising methodology for high-throughput generation of epitope-mapped monoclonal antibodies against AGE.
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| 20. |
- Wåhlén, Karin, 1986-, et al.
(author)
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Proteomic Investigation in Plasma from Women with Fibromyalgia in Response to a 15-wk Resistance Exercise Intervention
- 2022
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In: Medicine & Science in Sports & Exercise. - Philadelphia, PA, United States : Ovid Technologies (Wolters Kluwer Health). - 0195-9131 .- 1530-0315. ; 54:2, s. 232-246
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Journal article (peer-reviewed)abstract
- PurposeFibromyalgia (FM) is a complex pain condition, and exercise is considered the first option of treatment. Few studies have examined the effect of exercise on molecular mechanisms in FM. The aim of this study was to analyze the plasma proteome in women with FM and healthy controls (CON) before and after 15 wk of resistance exercise. This study further investigated whether clinical and exercises-related outcomes correlated with identified plasma proteins in FM.MethodsPlasma samples from 40 FM/25 CON (baseline) and 21 FM/24 CON (postexercise) were analyzed using shotgun proteomics. Clinical/background data were retrieved through questionnaires. Exercise-related variables and pressure pain thresholds were assessed using standardized instruments. Multivariate statistics were applied to analyze the proteomic profile at baseline and postexercise, and correlation with clinical/exercise-related data.ResultsFifteen weeks of resistance exercises improved clinical symptoms and muscle strength, and affected circulating proteins related to immunity, stress, mRNA stability, metabolic processes, and muscle structure development in FM. Pressure pain threshold was related to a specific protein profile, with proteins involved in metabolic and immune response. Subgroups of FM based on plasma proteins, FM duration, and improved muscle strength were identified.ConclusionsExercise seems to affect circulating proteins, clinical characteristics, and muscle strength in FM. This study contributes to better understanding of systemic protein changes in FM compared with CON and how resistance exercise affects such changes.
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| 21. |
- Åhsberg, Josefine, et al.
(author)
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Early B-cell Factor 1 Regulates the Expansion of B-cell Progenitors in a Dose-dependent Manner
- 2013
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In: Journal of Biological Chemistry. - : American Society for Biochemistry and Molecular Biology. - 0021-9258 .- 1083-351X. ; 288:46, s. 33449-33461
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Journal article (peer-reviewed)abstract
- Transcription factor doses are of importance for normal and malignant B-lymphocyte development; however, the understanding of underlying mechanisms and functional consequences of reduced transcription factor levels is limited. We have analyzed progenitor and B-lineage compartments in mice carrying heterozygote mutations in the E2a, Ebf1, or Pax5 gene. Although lymphoid progenitors from Ebf1 or Pax5 heterozygote mice were specified and lineage-restricted in a manner comparable with Wt progenitors, this process was severely impaired in E2a heterozygote mutant mice. This defect was not significantly enhanced upon combined deletion of E2a with Ebf1 or Pax5. Analysis of the pre-B-cell compartment in Ebf1 heterozygote mice revealed a reduction in cell numbers. These cells expressed Pax5 and other B-lineage-associated genes, and global gene expression analysis suggested that the reduction of the pre-B-cell compartment was a result of impaired pre-B-cell expansion. This idea was supported by a reduction in IL2R-expressing late pre-B-cells as well as by cell cycle analysis and by the finding that the complexity of the VDJ rearrangement patterns was comparable in Wt and Ebf1(+/-) pre-B-cells, although the number of progenitors was reduced. Heterozygote deletion of Ebf1 resulted in impaired response to IL7 in vitro and reduced expression levels of pre-BCR on the cell surface, providing possible explanations for the observed stage-specific reduction in cellular expansion. Thus, transcription factor doses are critical for specification as well as expansion of B-lymphoid progenitors, providing increased insight into the molecular regulation of B-cell development.
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