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Single-cell analysis of early B-lymphocyte development suggests independent regulation of lineage specification and commitment in vivo
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. 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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2012 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 39, 15871-15876 p.Article in journal (Refereed) Published
Abstract [en]

To better understand the process of B-lymphocyte lineage restriction, we have investigated molecular and functional properties in early B-lineage cells from Pax-5-deficient animals crossed to a B-lineage-restricted reporter mouse, allowing us to identify B-lineage-specified progenitors independently of conventional surface markers. Pax-5 deficiency resulted in a dramatic increase in the frequency of specified progenitor B-cellsmarked by expression of a lambda 5 (Igll1) promoter-controlled reporter gene. Gene expression analysis of ex vivo isolated progenitor cells revealed that Pax-5 deficiency has a minor impact on B-cell specification. However, single-cell in vitro differentiation analysis of ex vivo isolated cells revealed that specified B-lineage progenitors still displayed a high degree of plasticity for development into NK or T lineage cells. In contrast, we were unable to detect any major changes in myeloid lineage potential in specified Pax-5-deficient cells. By comparison of gene expression patterns in ex vivo isolated Pax-5-and Ebf-1-deficient progenitors, it was possible to identify a set of B-cell-restricted genes dependent on Ebf-1 but not Pax-5, supporting the idea that B-cell specification and commitment is controlled by distinct regulatory networks.

Place, publisher, year, edition, pages
National Academy of Sciences , 2012. Vol. 109, no 39, 15871-15876 p.
Keyword [en]
transcription, Notch-1, Deltex
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-85090DOI: 10.1073/pnas.1210144109ISI: 000309604500070OAI: oai:DiVA.org:liu-85090DiVA: diva2:564620
Note

Funding Agencies|Swedish Cancer Society||Swedish Research Council||Swedish Childhood Cancer Foundation||faculty of Medicine at Linkoping University||

Available from: 2012-11-02 Created: 2012-11-02 Last updated: 2017-12-07
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.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1422
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:liu:diva-114273 (URN)10.3384/diss.diva-114273 (DOI)978-91-7519-226-0 (ISBN)
Public defence
2014-12-12, Victoriasalen, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2015-02-16 Created: 2015-02-16 Last updated: 2016-06-22Bibliographically approved

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Zandi, SasanÅhsberg, JosefineTsapogas, PanagiotisQian, HongSigvardsson, Mikael

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