| 1. |
- Böiers, Charlotta, et al.
(författare)
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A Human IPS Model Implicates Embryonic B-Myeloid Fate Restriction as Developmental Susceptibility to B Acute Lymphoblastic Leukemia-Associated ETV6-RUNX1
- 2018
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Ingår i: Developmental Cell. - : Elsevier BV. - 1534-5807 .- 1878-1551. ; 44:3, s. 7-377
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Tidskriftsartikel (refereegranskat)abstract
- ETV6-RUNX1 is associated with childhood acute B-lymphoblastic leukemia (cALL) functioning as a first-hit mutation that initiates a clinically silent pre-leukemia in utero. Because lineage commitment hierarchies differ between embryo and adult, and the impact of oncogenes is cell-context dependent, we hypothesized that the childhood affiliation of ETV6-RUNX1 cALL reflects its origins in a progenitor unique to embryonic life. We characterize the first emerging B cells in first-trimester human embryos, identifying a developmentally restricted CD19−IL-7R+ progenitor compartment, which transitions from a myeloid to lymphoid program during ontogeny. This developmental series is recapitulated in differentiating human pluripotent stem cells (hPSCs), thereby providing a model for the initiation of cALL. Genome-engineered hPSCs expressing ETV6-RUNX1 from the endogenous ETV6 locus show expansion of the CD19−IL-7R+ compartment, show a partial block in B lineage commitment, and produce proB cells with aberrant myeloid gene expression signatures and potential: features (collectively) consistent with a pre-leukemic state. Böiers, Richardson et al. explore the potential for a developmental susceptibility to childhood acute lymphoblastic leukemia. Characterization of earliest B cell progenitors in human fetal liver identified a unique progenitor compartment that can be recapitulated using human pluripotent stem cells to model the impact of the pre-leukemia-initiating oncogene ETV6-RUNX1.
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| 2. |
- Drissen, Roy, et al.
(författare)
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Distinct myeloid progenitor-differentiation pathways identified through single-cell RNA sequencing
- 2016
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Ingår i: Nature Immunology. - : Springer Science and Business Media LLC. - 1529-2908 .- 1529-2916. ; 17:6, s. 666-676
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Tidskriftsartikel (refereegranskat)abstract
- According to current models of hematopoiesis, lymphoid-primed multi-potent progenitors (LMPPs) (Lin(-)Sca-1(+)c-Kit(+)CD34(+)Flt3(hi)) and common myeloid progenitors (CMPs) (Lin(-)Sca-1(+)c-Kit(+)CD34(+)CD41(hi)) establish an early branch point for separate lineage-commitment pathways from hematopoietic stem cells, with the notable exception that both pathways are proposed to generate all myeloid innate immune cell types through the same myeloid-restricted pre-granulocyte-macrophage progenitor (pre-GM) (Lin(-)Sca-1(-)c-Kit(+)CD41(-)FcγRII/III(-)CD150(-)CD105(-)). By single-cell transcriptome profiling of pre-GMs, we identified distinct myeloid differentiation pathways: a pathway expressing the gene encoding the transcription factor GATA-1 generated mast cells, eosinophils, megakaryocytes and erythroid cells, and a pathway lacking expression of that gene generated monocytes, neutrophils and lymphocytes. These results identify an early hematopoietic-lineage bifurcation that separates the myeloid lineages before their segregation from other hematopoietic-lineage potential.
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| 3. |
- Kristiansen, Trine A., et al.
(författare)
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Cellular Barcoding Links B-1a B Cell Potential to a Fetal Hematopoietic Stem Cell State at the Single-Cell Level
- 2016
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Ingår i: Immunity. - : Elsevier BV. - 1074-7613. ; 45:2, s. 346-357
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Tidskriftsartikel (refereegranskat)abstract
- Hematopoietic stem cells (HSCs) undergo a functional switch in neonatal mice hallmarked by a decrease in self-renewing divisions and entry into quiescence. Here, we investigated whether the developmental attenuation of B-1a cell output is a consequence of a shift in stem cell state during ontogeny. Using cellular barcoding for in vivo single-cell fate analyses, we found that fetal liver definitive HSCs gave rise to both B-1a and B-2 cells. Whereas B-1a potential diminished in all HSCs with time, B-2 output was maintained. B-1a and B-2 plasticity could be reinitiated in a subset of adult HSCs by ectopic expression of the RNA binding protein LIN28B, a key regulator of fetal hematopoiesis, and this coincided with the clonal reversal to fetal-like elevated self-renewal and repopulation potential. These results anchor the attenuation of B-1a cell output to fetal HSC behavior and demonstrate that the developmental decline in regenerative potential represents a reversible HSC state.
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| 4. |
- Renoux, Virginie, et al.
(författare)
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Identification of a Human Natural Killer Cell Lineage-Restricted Progenitor in Fetal and Adult Tissues.
- 2015
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Ingår i: Immunity. - : Elsevier BV. - 1074-7613 .- 1097-4180. ; 43:2, s. 394-407
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Tidskriftsartikel (refereegranskat)abstract
- Natural killer (NK) cells are cytotoxic lymphocytes and play a vital role in controlling viral infections and cancer. In contrast to B and T lymphopoiesis where cellular and regulatory pathways have been extensively characterized, the cellular stages of early human NK cell commitment remain poorly understood. Here we demonstrate that a Lin(-)CD34(+)CD38(+)CD123(-)CD45RA(+)CD7(+)CD10(+)CD127(-) population represents a NK lineage-restricted progenitor (NKP) in fetal development, umbilical cord blood, and adult tissues. The newly identified NKP has robust NK cell potential both in vitro and in vivo, generates functionally cytotoxic NK cells, and lacks the ability to produce T cells, B cells, myeloid cells, and innate lymphoid-like cells (ILCs). Our findings identify an early step to human NK cell commitment and provide new insights into the human hematopoietic hierarchy.
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| 5. |
- Zriwil, Alya, et al.
(författare)
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Direct role of FLT3 in regulation of early lymphoid progenitors
- 2018
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 183:4, s. 588-600
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Tidskriftsartikel (refereegranskat)abstract
- Given that FLT3 expression is highly restricted on lymphoid progenitors, it is possible that the established role of FLT3 in the regulation of B and T lymphopoiesis reflects its high expression and role in regulation of lymphoid-primed multipotent progenitors (LMPPs) or common lymphoid progenitors (CLPs). We generated a Flt3 conditional knock-out (Flt3fl/fl) mouse model to address the direct role of FLT3 in regulation of lymphoid-restricted progenitors, subsequent to turning on Rag1 expression, as well as potentially ontogeny-specific roles in B and T lymphopoiesis. Our studies establish a prominent and direct role of FLT3, independently of the established role of FLT3 in regulation of LMPPs and CLPs, in regulation of fetal as well as adult early B cell progenitors, and the early thymic progenitors (ETPs) in adult mice but not in the fetus. Our findings highlight the potential benefit of targeting poor prognosis acute B-cell progenitor leukaemia and ETP leukaemia with recurrent FLT3 mutations using clinical FLT3 inhibitors.
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| 6. |
- Zriwil, Alya, et al.
(författare)
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Macrophage colony-stimulating factor receptor marks and regulates a fetal myeloid-primed B-cell progenitor in mice
- 2016
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 128:2, s. 217-226
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Tidskriftsartikel (refereegranskat)abstract
- Although it is well established that unique B-cell lineages develop through distinct regulatory mechanisms during embryonic development, much less is understood about the differences between embryonic and adult B-cell progenitor cells, likely to underpin the genetics and biology of infant and childhood PreB acute lymphoblastic leukemia (PreB-ALL), initiated by distinct leukemia-initiating translocations during embryonic development. Herein, we establish that a distinct subset of the earliest CD19+ B-cell progenitors emerging in the E13.5 mouse fetal liver express the colony-stimulating factor-1 receptor (CSF1R), previously thought to be expressed, and play a lineage-restricted role in development of myeloid lineages, and macrophages in particular. These early embryonic CSF1R+CD19+ ProB cells also express multiple other myeloid genes and, in line with this, possess residual myeloid as well as B-cell, but not T-cell lineage potential. Notably, these CSF1R+ myeloid-primed ProB cells are uniquely present in a narrow window of embryonic fetal liver hematopoiesis and do not persist in adult bone marrow. Moreover, analysis of CSF1R-deficient mice establishes a distinct role of CSF1R in fetal B-lymphopoiesis. CSF1R+ myeloid-primed embryonic ProB cells are relevant for infant and childhood PreB-ALLs, which frequently have a bi-phenotypic B-myeloid phenotype, and in which CSF1R-rearrangements have recently been reported.
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| 7. |
- Zriwil, Alya
(författare)
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On the origin of B cells. Elucidating the Role of Tyrosine Kinase Receptors in B Cell Development.
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- B cells are essential cells that are part of the adaptive immune system with the capacity to produce antibodies against exogenous antigens. These cells are produced through a process called hematopoiesis, tightly regulated by extrinsic and intrinsic factors. Among these, tyrosine kinase receptors and their cytokines have been shown to have an important role in adult lymphopoiesis regulation. However, little is known about their involvement in the ontogeny of the blood system, and specifically, the B lineage that takes place in the embryo. In this thesis, I have aimed to deepen our understanding of the regulation and differentiation of hematopoietic cells in the embryo, both in mouse and human. In the first paper, we have identified a new distinct B cell progenitor in mouse that is uniquely present in a narrow window of fetal liver lymphopoiesis and that possesses B/myeloid potential and gene identity. We have also shown that the tyrosine kinase receptor, CSF1R, marks and regulates this progenitor and that upon loss of CSF1R signaling, embryonic B lymphopoiesis was specifically impaired. These CSF1R+ ProB progenitors are relevant for infant and childhood leukemia in which CSF1R has recently been found to be rearranged.In the second paper, we have demonstrated that the first CD19+ B cell emerging in the human embryo expresses IL7R and seems to derive from a newly identified IL7R+ progenitor. Using single cell gene expression analysis, we have shown that this IL7R+ progenitor shifts from a myeloid to a lympho-myeloid gene signature throughout development. Importantly, we have developed an in vitro modeling system that allowed us to recapitulate this transition and hierarchy using human pluripotent stem cells and used this system to study one of the most commonly found fusion genes, ETV6-RUNX1, in childhood B cell leukemia (B-ALL). Our investigation suggests that the IL7R+ progenitor can be a relevant target cell for in utero B-ALL, initiating pre-leukemic mutation.In the third paper, we have developed a new mouse model that allows a time or stage specific deletion of the tyrosine kinase receptor, FLT3. Previous loss of function studies, using mice deficient either for the receptor or for its ligand, FLT3L, have demonstrated that FLT3 signaling is required for lymphoid and also myeloid development. However, they have not been able to address the specific cellular stage of FLT3 requirement in the hematopoietic differentiation since the receptor was constitutively lost in the entire blood hierarchy and from the first HSC in the embryo. We showed here that FLT3 is required for adult hematopoiesis, and also after lymphoid commitment, while being dispensable after commitment to the B lineage.Overall, the papers included in this thesis highlight the need for studying embryonic hematopoiesis specifically, since regulatory requirements can change during ontogeny. It also shows the importance of developing new tools in order to study the onset of infant and childhood blood disorders that are thought to derive from mutations occurring already in utero.
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