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Interleukin-7-induced Stat-5 Acts in Synergy with Flt-3 Signaling to Stimulate Expansion of Hematopoietic Progenitor Cells
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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2010 (English)In: JOURNAL OF BIOLOGICAL CHEMISTRY, ISSN 0021-9258, Vol. 285, no 47, 36275-36284 p.Article in journal (Refereed) Published
Abstract [en]

The development of lymphoid cells from bone marrow progenitors is dictated by interplay between internal cues such as transcription factors and external signals like the cytokines Flt-3 ligand and Il-7. These proteins are both of large importance for normal lymphoid development; however, it is unclear if they act in direct synergy to expand a transient Il-7R(+)Flt-3(+) population or if the collaboration is created through sequential activities. We report here that Flt-3L and Il-7 synergistically stimulated the expansion of primary Il-7R(+)Flt-3(+) progenitor cells and a hematopoietic progenitor cell line ectopically expressing the receptors. The stimulation resulted in a reduced expression of pro-apoptotic genes and also mediated survival of primary progenitor cells in vitro. However, functional analysis of single cells suggested that the anti-apoptotic effect was additive indicating that the synergy observed mainly depends on stimulation of proliferation. Analysis of downstream signaling events suggested that although Il-7 induced Stat-5 phosphorylation, Flt-3L caused activation of the ERK and AKT signaling pathways. Flt-3L could also drive proliferation in synergy with ectopically expressed constitutively active Stat-5. This synergy could be inhibited with either receptor tyrosine kinase or MAPK inhibitors suggesting that Flt-3L and Il-7 act in synergy by activation of independent signaling pathways to expand early hematopoietic progenitors.

Place, publisher, year, edition, pages
The American Society for Biochemistry and Molecular Biology , 2010. Vol. 285, no 47, 36275-36284 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-62734DOI: 10.1074/jbc.M110.155531ISI: 000284146100037PubMedID: 20829349OAI: oai:DiVA.org:liu-62734DiVA: diva2:374227
Available from: 2010-12-03 Created: 2010-12-03 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.
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)
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Supervisors
Available from: 2015-02-16 Created: 2015-02-16 Last updated: 2016-06-22Bibliographically approved

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Åhsberg, JosefineTsapogas, PanagiotisQian, HongZetterblad, JennyZandi, SasanJönsson, Jan-IngvarSigvardsson, Mikael

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