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Early B-cell Factor 1 Regulates the Expansion of B-cell Progenitors in a Dose-dependent Manner
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
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2013 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 46, 33449-33461 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology , 2013. Vol. 288, no 46, 33449-33461 p.
Keyword [en]
Development; Differentiation; Immunology; Lymphocyte; Transcription Factors
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-103303DOI: 10.1074/jbc.M113.506261ISI: 000328841700057OAI: diva2:688478
Available from: 2014-01-17 Created: 2014-01-16 Last updated: 2015-02-16
In thesis
1. Molecular mechanisms in lymphoid restriction: securing the B lineage fate
Open this publication in new window or tab >>Molecular mechanisms in lymphoid restriction: securing the B lineage fate
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

With the work in this thesis I have aimed to deepen the understanding of the mechanisms behind the development of different blood cell lineages with a specific focus on B cell development.

To understand the interplay between extracellular signaling and transcription factor networks in early lymphoid development we investigated the functional collaborations of FLT3 and IL7R. We found that signaling via FLT3 and IL7R act in powerful synergy on proliferation of common lymphoid progenitors (CLPs). In addition to a role in expansion of progenitor cells we provided evidence for that IL7R signaling play a crucial role in B-cell commitment. IL7 deficient mice display a dramatic block in development before functional lineage restriction in the Ly6D+ CLP-compartment. The few Ly6D+CLPs that do develop have reduced mRNA levels of transcription factor EBF1, a protein with crucial functions in lineage restriction and activation of the B-lymphoid program. One crucial function of EBF1 is to activate Pax5. Even though Pax5 deficient fetal liver cells upon transplantation to congenic hosts will generate an abundance of cells with an activated B-lineage transcriptional program, the pro-B cells have disrupted regulation of non-B-lineage transcripts and a propensity to develop into T- and NK-cells in vitro. Both the activation of the B-lineage program and lineage restriction was dependent on the dose of transcription factors. Mice carrying a heterozygous mutation for the transcription factor E2A had slightly reduced relative frequency of progenitor cells and an impaired B-lineage specification in CLPs. Loss of one allele of Ebf1 resulted in reduced surface expression of IL2Rα and pre-B cell receptor (BCR), reduced IL7-response in vitro, and disrupted cell cycle dynamics in pro- and pre-B cells. While heterozygous loss of Pax5 did not result in any dramatic phenotype,  the combined loss of one allele of Pax5 and one allele of Ebf1 (Pax5+/-Ebf1+/-) had a dramatic effect on lineage plasticity in B-cell progenitors compared to the single heterozygotes. Furthermore, these Pax5+/-Ebf1+/- mice developed spontaneous, transplantable pro-B cell tumors and had a significantly reduced probability to survive over time. The transformed cells show high in vitro plasticity and tumor cells with induced overexpression of intracellular Notch1 can transform into T-lineage cell in vivo.

The data presented in this thesis add important pieces of information to the field of developmental hematopoiesis. By increasing the analytical depth of development in normal circumstances, and by understanding the consequence of genetic mutations in relation to cell type, we hope to contribute to the understanding of hematopoietic development in health and disease.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. 55 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1422
National Category
Microbiology in the medical area
urn:nbn:se:liu:diva-114273 (URN)10.3384/diss.diva-114273 (DOI)978-91-7519-226-0 (print) (ISBN)
Public defence
2014-12-12, Victoriasalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Available from: 2015-02-16 Created: 2015-02-16 Last updated: 2016-06-22Bibliographically approved

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Åhsberg, JosefineUngerbäck, JonasStrid, TobiasWelinder, EvaLarsson, MalinQian, HongSigvardsson, Mikael
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Division of Microbiology and Molecular MedicineFaculty of Health SciencesExperimental HematologyBioinformaticsThe Institute of Technology
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