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  • 1.
    Mansson, Robert
    et al.
    University of California, San Diego, USA .
    Welinder, Eva
    University of California, San Diego, USA .
    Åhsberg, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Lin, Yin C.
    University of California, San Diego, USA .
    Benner, Christopher
    University of California, San Diego, USA .
    Glass, Christopher K.
    University of California, San Diego, USA .
    Lucas, Joseph S.
    University of California, San Diego, USA .
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Murre, Cornelis
    University of California, San Diego, USA .
    Positive intergenic feedback circuitry, involving EBF1 and FOXO1, orchestrates B-cell fate2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 51, p. 21028-21033Article in journal (Refereed)
    Abstract [en]

    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.

  • 2. Prasad, Mahadesh A. J.
    et al.
    Ungerbäck, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Åhsberg, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Somasundaram, Rajesh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Strid, Tobias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Larsson, Malin
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Mansson, Robert
    Karolinska Institute, Sweden.
    De Paepe, Ayla
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, Faculty of Science & Engineering.
    Lilljebjorn, Henrik
    Lund University, Sweden.
    Fioretos, Thoas
    Lund University, Sweden.
    Hagman, James
    National Jewish Heatlh, CO USA.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Ebf1 heterozygosity results in increased DNA damage in pro-B cells and their synergistic transformation by Pax5 haploinsufficiency2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 125, no 26, p. 4052-4059Article in journal (Refereed)
    Abstract [en]

    Early B-cell factor 1 (Ebf1) is a transcription factor with documented dose-dependent functions in normal and malignant B-lymphocyte development. To understand more about the roles of Ebf1 in malignant transformation, we investigated the impact of reduced functional Ebf1 dosage on mouse B-cell progenitors. Gene expression analysis suggested that Ebf1 was involved in the regulation of genes important for DNA repair and cell survival. Investigation of the DNA damage in steady state, as well as after induction of DNA damage by UV light, confirmed that pro-B cells lacking 1 functional allele of Ebf1 display signs of increased DNA damage. This correlated to reduced expression of DNA repair genes including Rad51, and chromatin immunoprecipitation data suggested that Rad51 is a direct target for Ebf1. Although reduced dosage of Ebf1 did not significantly increase tumor formation in mice, a dramatic increase in the frequency of pro-B cell leukemia was observed in mice with combined heterozygous mutations in the Ebf1 and Pax5 genes, revealing a synergistic effect of combined dose reduction of these proteins. Our data suggest that Ebf1 controls DNA repair in a dose-dependent manner providing a possible explanation to the frequent involvement of EBF1 gene loss in human leukemia.

  • 3.
    Sigvardsson, Mikael
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Zandi, Sasan
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Åhsberg, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Qian, Hong
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Stjenrberg, Jenny
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Distinct regulatory networks control B-lymphoid specification and lineage commitment in JOURNAL OF IMMUNOLOGY, vol 188, issue , pp2012In: JOURNAL OF IMMUNOLOGY, American Association of Immunologists , 2012, Vol. 188Conference paper (Refereed)
    Abstract [en]

    n/a

  • 4.
    Tang, Yan-juan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Halvarsson, Camilla
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Nordigården, Amanda
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Kumar, Komal
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Åhsberg, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Rörby, Emma
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Man Wong, Wan
    Lund University, Sweden.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Coexpression of hyperactivated AKT1 with additional genes activated in leukemia drives hematopoietic progenitor cells to cell cycle block and apoptosis2015In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 43, no 7, p. 554-564Article in journal (Refereed)
    Abstract [en]

    The phosphatidylinositol 3-kinase/AKT pathway is an integral component of signaling involved in the development of many cancers, including myeloid leukemias such as chronic myeloid leukemia and acute myeloid leukemia (AML). Increased AKT1 activity is frequently seen in AML patients, providing leukemic cells with growth and survival promoting signals. An important aspect of AKT1 function is its involvement in cellular metabolism and energy production. Under some circumstances, strong activation of AKT1 increases oxidative stress, which can cause apoptosis when cells progressively build up excess free radicals. This has been described in hematopoietic cells overexpressing activated AKT1; however, whether this is true in cells coexpressing other genetic events involved in leukemia is not known. This prompted us to investigate the effect of constitutively active AKT1 (myristoylated AKT1) in hematopoietic progenitor cells expressing constitutively active signal transducer and activator of transcription 5, Fms-related tyrosine kinase 3-internal tandem duplication, or antiapoptotic B-cell lymphoma 2. Surprisingly, myristoylated AKT1 was incompatible with proliferation driven by both signal transducer and activator of transcription 5 and Fms-related tyrosine kinase 3-internal tandem duplication, which triggered cell cycle block and apoptosis. Moreover, transplantable cells of B-cell lymphoma 2-transgenic mice were impaired in their engraftment ability to recipient mice when expressing hyperactivated AKT1. This Was linked to AKT1-mediated proapoptotic functions and not to impairment in homing to the bone marrow. Although cells expressing hyperactivated AKT1 displayed higher levels of reactive oxygen species both in vitro and in vivo, the addition of the antioxidant N-acetyl-L-cysteine significantly reduced apoptosis. Taken together, the results indicate that constitutive AKT1 activity is incompatible with growth- and survival-promoting ability of other activated genes in AML. Copyright (C) 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc.

  • 5.
    Tang, Yanjuan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Halvarsson, Camilla
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Nordigården, Amanda
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Åhsberg, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Wong, Wan Man
    Lund Strategic Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Hyperactivated AKT is incompatible with survival when coexpressed with additional oncogenes and drives hematopoietic stem and progenitor cells to cell cycle inhibition and apoptosisManuscript (preprint) (Other academic)
    Abstract [en]

    The PI3K-AKT signaling pathway plays an important role in cell growth and metabolism. Increased AKT activity is frequently seen in patients with acute myeloid leukemia (AML), providing leukemic cells with both growth-promoting and survival signals involved in the transformation process. In AML up to 30% of all patients carry activating mutations in the tyrosine kinase receptor FLT3, leading to activation of the PI3K/AKT pathway as well as STAT5. Here, we investigated the effect of hyperactivated AKT (myristylated AKT) by retroviral transfer to hematopoietic progenitor cells coexpressing STAT5, FLT3-ITD, or antiapoptotic Bcl-2. AKT was unable to relieve cytokine-dependence. Surprisingly, uncontrolled AKT activity was linked to accumulation of cells in the G0 stage of the cell cycle and increased cell numbers became apoptotic. Hyperactivated AKT was incompatible with STAT5-driven proliferation and triggered apoptosis. The same was true also in FLT3-ITDexpressing progenitor cells of transgenic mice. Transplantable hematopoietic stem cells of wildtype and Bcl-2 transgenic mice were impaired in their engraftment ability to recipient mice when expressing hyperactivated AKT. This was linked to AKT-mediated pro-apoptotic functions and not due to effects on homing or migration. Cells expressing hyperactivated AKT displayed higher levels of reactive oxygen species. However, the addition of the antioxidant N-acetyl-L-lysine significantly reduced apoptosis. Taken together, the results indicate that constitutive AKT activity is incompatible with the growth- and survivalpromoting ability of FLT3-ITD and its downstream targets. These findings may provide a novel tool to intervene with AKT activity in leukemia.

  • 6.
    Tsapogas, Panagiotis
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Zandi, Sasan
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Åhsberg, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Welinder, Eva
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Månsson, Robert
    Department for Hematopoietic Stem cell Biology. Lund Stem Cell Center. BMC B12, 221 84 Lund, Sweden.
    Qian, Hong
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences.
    Functional and molecular analysis of B-lineage commitment suggests an instructive role for Il-7 in the earliest lymphoid restricted cellsManuscript (preprint) (Other academic)
    Abstract [en]

    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.

  • 7.
    Tsapogas, Panagiotis
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Zandi, Sasan
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Åhsberg, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Zetterblad, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Welinder, Eva
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Mansson, Robert
    Lund University.
    Qian, Hong
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    IL-7 mediates Ebf-1-dependent lineage restriction in early lymphoid progenitors2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 5, p. 1283-1290Article in journal (Refereed)
    Abstract [en]

    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.

  • 8.
    Ungerbäck, Jonas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Åhsberg, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Strid, Tobias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Somasundaram, Rajesh
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Combined heterozygous loss of Ebf1 and Pax5 allows for T-lineage conversion of B cell progenitors2015In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 212, no 7, p. 1109-1123Article in journal (Refereed)
    Abstract [en]

    To investigate how transcription factor levels impact B-lymphocyte development, we generated mice carrying transheterozygous mutations in the Pax5 and Ebf1 genes. Whereas combined reduction of Pax5 and Ebf1 had minimal impact on the development of the earliest CD19(+) progenitors, these cells displayed an increased T cell potential in vivo and in vitro. The alteration in lineage fate depended on a Notch1-mediated conversion process, whereas no signs of de-differentiation could be detected. The differences in functional response to Notch signaling in Wt and Pax5(+/-) Ebf1(+/-) pro-B cells were reflected in the transcriptional response. Both genotypes responded by the generation of intracellular Notch1 and activation of a set of target genes, but only the Pax5(+/-) Ebf1(+/-) pro-B cells down-regulated genes central for the preservation of stable B cell identity. This report stresses the importance of the levels of transcription factor expression during lymphocyte development, and suggests that Pax5 and Ebf1 collaborate to modulate the transcriptional response to Notch signaling. This provides an insight on how transcription factors like Ebf1 and Pax5 preserve cellular identity during differentiation.

  • 9.
    Welinder, Eva
    et al.
    Lund Stem Cell Center, BMC B10, Lund.
    Åhsberg, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    B-lymphocyte commitment: Identifying the point of no return2011In: Seminars in Immunology, ISSN 1044-5323, E-ISSN 1096-3618, Vol. 23, no 5, p. 335-340Article, review/survey (Refereed)
    Abstract [en]

    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.

  • 10.
    Zandi, Sasan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Åhsberg, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Tsapogas, Panagiotis
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Stjernberg, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Qian, Hong
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Single-cell analysis of early B-lymphocyte development suggests independent regulation of lineage specification and commitment in vivo2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 39, p. 15871-15876Article in journal (Refereed)
    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.

  • 11.
    Åhsberg, Josefine
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Molecular mechanisms in lymphoid restriction: securing the B lineage fate2014Doctoral 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.

    List of papers
    1. Interleukin-7-induced Stat-5 Acts in Synergy with Flt-3 Signaling to Stimulate Expansion of Hematopoietic Progenitor Cells
    Open this publication in new window or tab >>Interleukin-7-induced Stat-5 Acts in Synergy with Flt-3 Signaling to Stimulate Expansion of Hematopoietic Progenitor Cells
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    2010 (English)In: JOURNAL OF BIOLOGICAL CHEMISTRY, ISSN 0021-9258, Vol. 285, no 47, p. 36275-36284Article 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
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-62734 (URN)10.1074/jbc.M110.155531 (DOI)000284146100037 ()20829349 (PubMedID)
    Available from: 2010-12-03 Created: 2010-12-03 Last updated: 2015-02-16
    2. IL-7 mediates Ebf-1-dependent lineage restriction in early lymphoid progenitors
    Open this publication in new window or tab >>IL-7 mediates Ebf-1-dependent lineage restriction in early lymphoid progenitors
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    2011 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 5, p. 1283-1290Article in journal (Refereed) Published
    Abstract [en]

    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.

    Place, publisher, year, edition, pages
    American Society of Hematology, 2011
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-70104 (URN)10.1182/blood-2011-01-332189 (DOI)000293510000020 ()
    Available from: 2011-08-19 Created: 2011-08-19 Last updated: 2017-12-08
    3. Single-cell analysis of early B-lymphocyte development suggests independent regulation of lineage specification and commitment in vivo
    Open this publication in new window or tab >>Single-cell analysis of early B-lymphocyte development suggests independent regulation of lineage specification and commitment in vivo
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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, p. 15871-15876Article 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
    Keywords
    transcription, Notch-1, Deltex
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-85090 (URN)10.1073/pnas.1210144109 (DOI)000309604500070 ()
    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
    4. Early B-cell Factor 1 Regulates the Expansion of B-cell Progenitors in a Dose-dependent Manner
    Open this publication in new window or tab >>Early B-cell Factor 1 Regulates the Expansion of B-cell Progenitors in a Dose-dependent Manner
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    2013 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 46, p. 33449-33461Article 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
    Keywords
    Development; Differentiation; Immunology; Lymphocyte; Transcription Factors
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:liu:diva-103303 (URN)10.1074/jbc.M113.506261 (DOI)000328841700057 ()
    Available from: 2014-01-17 Created: 2014-01-16 Last updated: 2019-02-11
  • 12.
    Åhsberg, Josefine
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Tsapogas, Panagiotis
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Qian, Hong
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Zetterblad, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Zandi, Sasan
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Mansson, Robert
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Jönsson, Jan-Ingvar
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Interleukin-7-induced Stat-5 Acts in Synergy with Flt-3 Signaling to Stimulate Expansion of Hematopoietic Progenitor Cells2010In: JOURNAL OF BIOLOGICAL CHEMISTRY, ISSN 0021-9258, Vol. 285, no 47, p. 36275-36284Article in journal (Refereed)
    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.

  • 13.
    Åhsberg, Josefine
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Ungerbäck, Jonas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Strid, Tobias
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Welinder, Eva
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Stjernberg, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
    Larsson, Malin
    Linköping University, Department of Physics, Chemistry and Biology, Bioinformatics. Linköping University, The Institute of Technology.
    Qian, Hong
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Sigvardsson, Mikael
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Health Sciences.
    Early B-cell Factor 1 Regulates the Expansion of B-cell Progenitors in a Dose-dependent Manner2013In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 46, p. 33449-33461Article in journal (Refereed)
    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.

1 - 13 of 13
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