| 1. |
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| 2. |
- 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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| 3. |
- Böiers, Charlotta, et al.
(författare)
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Expression and role of FLT3 in regulation of the earliest stage of normal granulocyte-monocyte progenitor development.
- 2010
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; May 4, s. 5061-5068
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Tidskriftsartikel (refereegranskat)abstract
- Mice deficient in FLT3 signalling have reductions in early multipotent and lymphoid progenitors, whereas no evident myeloid phenotype has been reported. However, activating mutations of Flt3 are among the most common genetic events in acute myeloid leukemia and mice harbouring internal tandem duplications within Flt3 (Flt3-ITD) develop myeloproliferative disease, with characteristic expansion of granulocyte-monocyte (GM) progenitors, possibly compatible with FLT3-ITD promoting a myeloid fate of multipotent progenitors. Alternatively, FLT3 might be expressed at the earliest stages of GM development. Herein, we investigated the expression, function and role of FLT3 in recently identified early GM progenitors. Flt3-cre fate mapping established that most progenitors and mature progeny of the GM lineage are derived from Flt3 expressing progenitors. A higher expression of FLT3 was found in preGMP compared to GMP, and preGMPs were more responsive to stimulation with FLT3 ligand (FL). Whereas preGMPs and GMPs were reduced in Fl(-/-) mice, megakaryocyte-erythroid progenitors were unaffected and lacked FLT3 expression. Notably, mice deficient in both Thrombopoietin (THPO) and FL, had a more pronounced GM progenitor phenotype than Thpo(-/-) mice, establishing a role of FL in THPO-dependent and independent regulation of GM progenitors, of likely significance for myeloid malignancies with Flt3-ITD mutations.
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| 4. |
- Böiers, Charlotta, et al.
(författare)
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Lymphomyeloid Contribution of an Immune-Restricted Progenitor Emerging Prior to Definitive Hematopoietic Stem Cells.
- 2013
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Ingår i: Cell Stem Cell. - : Elsevier BV. - 1934-5909 .- 1875-9777. ; 13:5, s. 535-548
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Tidskriftsartikel (refereegranskat)abstract
- In jawed vertebrates, development of an adaptive immune-system is essential for protection of the born organism against otherwise life-threatening pathogens. Myeloid cells of the innate immune system are formed early in development, whereas lymphopoiesis has been suggested to initiate much later, following emergence of definitive hematopoietic stem cells (HSCs). Herein, we demonstrate that the embryonic lymphoid commitment process initiates earlier than previously appreciated, prior to emergence of definitive HSCs, through establishment of a previously unrecognized entirely immune-restricted and lymphoid-primed progenitor. Notably, this immune-restricted progenitor appears to first emerge in the yolk sac and contributes physiologically to the establishment of lymphoid and some myeloid components of the immune-system, establishing the lymphomyeloid lineage restriction process as an early and physiologically important lineage-commitment step in mammalian hematopoiesis.
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| 5. |
- Böiers, Charlotta
(författare)
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The Road to Maturity - Lineage Commitment in early Hematopoiesis
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The road to maturity – how do hematopoietic stem cells (HSC) differentiate into mature blood cells? The pathways of lineage commitment during normal hematopoiesis are of great significance in order to understand the underlying events that lead to leukemia, and to the design of proper treatments for prevention and remission of the disease. The route of hematopoiesis can be thought of as a hierarchical tree, with the rare HSCs at the top, transitioning down along the pathways as different progenitors. These progenitors continue on their way to become mature blood cells. The roads of blood cell production have been extensively studied in the adult mouse model, whereas less is known about the differentiation of cells during fetal mapping. It is not even known if blood cell commitment follows the same route in adult as in fetal life. The fetal map may be even more important to study since some pre-leukemic events are of prenatal origin. This thesis focuses on the role of different cytokines in lineage commitment, as well as on identifying the first lymphoid committed progenitor in the early fetus. The c-fms like tyrosine kinase 3 receptor (Flt3) is known to be important for lymphopoiesis. However, Flt3 is often found mutated in acute myeloid leukemia (AML), and then associated with poor prognosis. Despite the role in AML, no role for Flt3 or its ligand has been found in myelopoiesis. But more distinct stages of early myeloid progenitors can now be identified, and the role of Flt3 in myelopoiesis could be investigated in detail. We found that early myeloid progenitors express high levels of Flt3, and in mice deficient in Flt3 signaling myeloid progenitors are reduced. Taken together the data clearly show a role of Flt3 signaling in early myelopoiesis, which has implications for understanding the role of Flt3 mutations in AML. In the next study the key cytokines in B lymphopoiesis were investigated. The role of Flt3 signaling together with interleukin 7 (IL7) and a cytokine called Thymic stromal lymphopoietin (TSLP) was studied. TSLP has been suggested to have a key role in IL7 independent B cell development, although direct evidence has been lacking. By using different knockout mice the role of the three signaling pathways was investigated side by side in fetal and adult mice. Mice deficient in all three signaling pathways lacked B cells, as did mice deficient in IL7 and Flt3 signaling. The conclusion is that the IL7 and Flt3 signaling pathways are the main factors driving both fetal and adult B lymphopoiesis. In fetal hematopoiesis, as mentioned previously, the road to maturity is not well understood. We aimed at identifying the first lymphoid commitment step in the early embryo. A population in the fetal liver at 11.5 days post coitus (dpc), expressing the markers Flt3 and IL7 receptor alfa (IL7Rα), was purified. It was shown to have combined lymphoid and granulocyte/macrophage potential but no megakaryocyte or erythroid potential at the single cell level. This population could represent the first lympho-myeloid restricted cells in ontogeny, and further evidence suggests that it might be the first progenitor that seeds the thymus. By using a reporter mouse for recombination activating gene 1, Rag1, (an early sign of lymphoid commitment), a lympho-myeloid restricted population, expressing IL7Rα and Rag1-GFP, could be traced back to 9.5 dpc. Fetal liver colonization has been shown to begin at 9.5 dpc and definitive adult HSCs appear first one day later at 10.5 dpc. This study identifies a lymphomyeloid restricted progenitor in the early embryo, notably arising prior to the establishment of definitive HSCs, and suggests that lymphoid commitment might take place outside the fetal liver niche.
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| 6. |
- Guibentif, Carolina, et al.
(författare)
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Single-Cell Analysis Identifies Distinct Stages of Human Endothelial-to-Hematopoietic Transition
- 2017
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 19:1, s. 10-19
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Tidskriftsartikel (refereegranskat)abstract
- During development, hematopoietic cells originate from endothelium in a process known as endothelial-to-hematopoietic transition (EHT). To study human EHT, we coupled flow cytometry and single-cell transcriptional analyses of human pluripotent stem cell-derived CD34(+) cells. The resulting transcriptional hierarchy showed a continuum of endothelial and hematopoietic signatures. At the interface of these two signatures, a unique group of cells displayed both an endothelial signature and high levels of key hematopoietic stem cell-associated genes. This interphase group was validated via sort and subculture as an immediate precursor to hematopoietic cells. Differential expression analyses further divided this population into subgroups, which, upon subculture, showed distinct hematopoietic lineage differentiation potentials. We therefore propose that immediate precursors to hematopoietic cells already have their hematopoietic lineage restrictions defined prior to complete downregulation of the endothelial signature. These findings increase our understanding of the processes of de novo hematopoietic cell generation in the human developmental context.
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| 7. |
- Jensen, Christina, et al.
(författare)
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FLT3 ligand and not TSLP is the key regulator of IL-7-independent B-1 and B-2 B Lymphopoiesis.
- 2008
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 112, s. 2297-2304
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Tidskriftsartikel (refereegranskat)abstract
- Phenotypically and functionally distinct progenitors and developmental pathways have been proposed to exist for fetally-derived B-1 and conventional B-2 cells. Although IL-7 appears to be the primary regulator of fetal and adult B lymphopoiesis in mice, considerable fetal B lymphopoiesis and postnatal B-cells are sustained in the absence of IL-7, and in man B-cell generation is suggested to be largely or entirely IL-7-independent, as severe combined immune-deficient patients with IL-7-deficiency appear to have normal B-cell numbers. However, the role of other cytokines in IL-7-independent B lymphopoiesis remains to be established. Although thymic stromal lymphopoietin (TSLP) has been proposed to be the main factor driving IL-7-independent B lymphopoiesis, and to distinguish fetal from adult B-cell progenitor development in mice, recent studies failed to support a primary role of TSLP in IL-7-independent fetal B-cell development. However, the role of TSLP in IL-7-independent adult B lymphopoiesis and in particular in regulation of B-1 cells remains to be established. Herein, we demonstrate that rather than TSLP, IL-7 and FLT3 ligand (FLT3L) are combined responsible for all B-cell generation in mice, including recently identified B-1-specified cell progenitors. Thus, the same IL-7 and FLT3L-mediated signaling regulate alternative cellular pathways of fetal and adult B-1 and B-2 B lymphopoiesis.
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| 8. |
- Jensen, Christina, et al.
(författare)
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Permissive roles of hematopoietin and cytokine tyrosine kinase receptors in early T-cell development
- 2008
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Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 111:4, s. 2083-2090
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Tidskriftsartikel (refereegranskat)abstract
- Although several cytokines have been demonstrated to be critical regulators of development of multiple blood cell lineages, it remains disputed to what degree they act through instructive or permissive mechanisms. Signaling through the FMS-like tyrosine kinase 3 (FLT3) receptor and the hematopoietin IL-7 receptor alpha (IL-7Ralpha) has been demonstrated to be of critical importance for sustained thymopoiesis. Signaling triggered by IL-7 and thymic stromal lymphopoietin (TSLP) is dependent on IL-7Ralpha, and both ligands have been implicated in T-cell development. However, we demonstrate that, whereas thymopoiesis is abolished in adult mice doubly deficient in IL-7 and FLT3 ligand (FLT3L), TSLP does not play a key role in IL-7-independent or FLT3L-independent T lymphopoiesis. Furthermore, whereas previous studies implicated that the role of other cytokine tyrosine kinase receptors in T lymphopoiesis might not involve permissive actions, we demonstrate that ectopic expression of BCL2 is sufficient not only to partially correct the T-cell phenotype of Flt3l(-/-) mice but also to rescue the virtually complete loss of all discernable stages of early T lymphopoiesis in Flt3l(-/-)Il7r(-/-) mice. These findings implicate a permissive role of cytokine receptors of the hematopoietin and tyrosine kinase families in early T lymphopoiesis.
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| 9. |
- Jensen, Christina, et al.
(författare)
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TSLP-mediated fetal B lymphopoiesis?
- 2007
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Ingår i: Nature Immunology. - : Springer Science and Business Media LLC. - 1529-2908 .- 1529-2916. ; 8:9, s. 897-897
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Tidskriftsartikel (refereegranskat)
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| 10. |
- Karlsson, Göran, et al.
(författare)
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Defining the Emerging Blood System During Development at Single-Cell Resolution
- 2021
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Ingår i: Frontiers in Cell and Developmental Biology. - : Frontiers Media SA. - 2296-634X. ; 9
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Forskningsöversikt (refereegranskat)abstract
- Developmental hematopoiesis differs from adult and is far less described. In the developing embryo, waves of lineage-restricted blood precede the ultimate emergence of definitive hematopoietic stem cells (dHSCs) capable of maintaining hematopoiesis throughout life. During the last two decades, the advent of single-cell genomics has provided tools to circumvent previously impeding characteristics of embryonic hematopoiesis, such as cell heterogeneity and rare cell states, allowing for definition of lineage trajectories, cellular hierarchies, and cell-type specification. The field has rapidly advanced from microfluidic platforms and targeted gene expression analysis, to high throughput unbiased single-cell transcriptomic profiling, single-cell chromatin analysis, and cell tracing-offering a plethora of tools to resolve important questions within hematopoietic development. Here, we describe how these technologies have been implemented to address a wide range of aspects of embryonic hematopoiesis ranging from the gene regulatory network of dHSC formation via endothelial to hematopoietic transition (EHT) and how EHT can be recapitulated in vitro, to hematopoietic trajectories and cell fate decisions. Together, these studies have important relevance for regenerative medicine and for our understanding of genetic blood disorders and childhood leukemias.
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