| 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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| 11. |
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| 12. |
- Kharazi, Shabnam, et al.
(författare)
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Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 118:13, s. 3613-3621
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Tidskriftsartikel (refereegranskat)abstract
- Acquisition of homozygous activating growth factor receptor mutations might accelerate cancer progression through a simple gene-dosage effect. Internal tandem duplications (ITDs) of FLT3 occur in approximately 25% cases of acute myeloid leukemia and induce ligand-independent constitutive signaling. Homozygous FLT3-ITDs confer an adverse prognosis and are frequently detected at relapse. Using a mouse knockin model of Flt3-internal tandem duplication (Flt3-ITD)-induced myeloproliferation, we herein demonstrate that the enhanced myeloid phenotype and expansion of granulocyte-monocyte and primitive Lin(-)Sca1(+)c-Kit(+) progenitors in Flt3-ITD homozygous mice can in part be mediated through the loss of the second wild-type allele. Further, whereas autocrine FLT3 ligand production has been implicated in FLT3-ITD myeloid malignancies and resistance to FLT3 inhibitors, we demonstrate here that the mouse Flt3(ITD/ITD) myeloid phenotype is FLT3 ligand-independent. (Blood. 2011; 118(13):3613-3621)
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| 13. |
- Luc, Sidinh, et al.
(författare)
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Downregulation of Mpl marks the transition to lymphoid-primed multipotent progenitors with gradual loss of granulocyte-monocyte potential.
- 2008
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 111:7, s. 3424-3434
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Tidskriftsartikel (refereegranskat)abstract
- Evidence for a novel route of adult hematopoietic stem cell lineage commitment through Lin(-)Sca-1(+)Kit(+)Flt3(hi) (LSKFlt3(hi)) lymphoid-primed multipotent progenitors (LMPPs) with granulocyte/monocyte (GM) and lymphoid but little or no megakaryocyte/erythroid (MkE) potential was recently challenged, as LSKFlt3(hi) cells were reported to possess MkE potential. Herein residual (1-2%) MkE potential segregated almost entirely with LSKFlt3(hi) cells expressing the thrombopoietin receptor (Mpl), whereas LSKFlt3(hi)Mpl(-) LMPPs lacked significant MkE potential in vitro and in vivo, but sustained combined GM and lymphoid potentials, and co-expressed GM and lymphoid but not MkE transcriptional lineage programs. Gradually increased transcriptional lymphoid priming in single LMPPs from Rag1(GFP) mice was shown to occur in the presence of maintained GM lineage priming, but gradually reduced GM lineage potential. These functional and molecular findings reinforce the existence of GM/lymphoid restricted progenitors with dramatically downregulated probability for committing towards MkE fates, and support that lineage restriction occurs through gradual rather than abrupt changes in specific lineage potentials.
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| 14. |
- Luis, Tiago C., et al.
(författare)
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Initial seeding of the embryonic thymus by immune-restricted lympho-myeloid progenitors
- 2016
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Ingår i: Nature Immunology. - : Springer Science and Business Media LLC. - 1529-2908 .- 1529-2916. ; 17:12, s. 1424-1435
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Tidskriftsartikel (refereegranskat)abstract
- The final stages of restriction to the T cell lineage occur in the thymus after the entry of thymus-seeding progenitors (TSPs). The identity and lineage potential of TSPs remains unclear. Because the first embryonic TSPs enter a non-vascularized thymic rudiment, we were able to directly image and establish the functional and molecular properties of embryonic thymopoiesis-initiating progenitors (T-IPs) before their entry into the thymus and activation of Notch signaling. T-IPs did not include multipotent stem cells or molecular evidence of T cell-restricted progenitors. Instead, single-cell molecular and functional analysis demonstrated that most fetal T-IPs expressed genes of and had the potential to develop into lymphoid as well as myeloid components of the immune system. Moreover, studies of embryos deficient in the transcriptional regulator RBPJ demonstrated that canonical Notch signaling was not involved in pre-thymic restriction to the T cell lineage or the migration of T-IPs.
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| 15. |
- Richardson, Simon E., et al.
(författare)
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In vitro differentiation of human pluripotent stem cells into the B lineage using OP9-MS5 co-culture
- 2021
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Ingår i: STAR Protocols. - : Elsevier BV. - 2666-1667. ; 2:2
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Tidskriftsartikel (refereegranskat)abstract
- In vitro differentiation of human pluripotent stem cells (hPSCs) offers a genetically tractable system to examine the physiology and pathology of human tissue development and differentiation. We have used this approach to model the earliest stages of human B lineage development and characterize potential target cells for the in utero initiation of childhood B acute lymphoblastic leukemia. Herein, we detail critical aspects of the protocol including reagent validation, controls, and examples of surface markers used for analysis and cell sorting. For complete details on the use and execution of this protocol, please refer to Boiers et al. (2018).
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| 16. |
- Rippe, Catarina, et al.
(författare)
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Effect of high-fat diet, surrounding temperature, and enterostatin on uncoupling protein gene expression
- 2000
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Ingår i: American Journal of Physiology: Endocrinology and Metabolism. - 1522-1555. ; 279:2, s. 293-300
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Tidskriftsartikel (refereegranskat)abstract
- Nonshivering thermogenesis induced in brown adipose tissue (BAT) during high-fat feeding is mediated through uncoupling protein 1 (UCP1). UCP2 is a recently identified homologue found in many tissues. To determine the role of UCP1 and UCP2 in thermoregulation and energy balance, we investigated the long-term effect of high-fat feeding on mRNA levels in mice at two different ambient temperatures. We also treated mice with the anorectic peptide enterostatin and compared mRNA levels in BAT, white adipose tissue (WAT), stomach, and duodenum. Here, we report that high-fat feeding at 23 degrees C increased UCP1 and UCP2 levels in BAT four- and threefold, respectively, and increased UCP2 levels fourfold in WAT. However, at 29 degrees C, UCP1 decreased, whereas UCP2 remained unchanged in BAT and increased twofold in WAT. Enterostatin increased UCP1 and decreased UCP2 mRNA in BAT. In stomach and duodenum, high-fat feeding decreased UCP2 mRNA, whereas enterostatin increased it. Our results suggest that the regulation of uncoupling protein mRNA levels by high-fat feeding is dependent on ambient temperature and that enterostatin is able to modulate it.
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| 17. |
- Safi, Fatemeh, et al.
(författare)
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Concurrent stem- and lineage-affiliated chromatin programs precede hematopoietic lineage restriction
- 2022
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 39:6
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Tidskriftsartikel (refereegranskat)abstract
- The emerging notion of hematopoietic stem and progenitor cells (HSPCs) as a low-primed cloud without sharply demarcated gene expression programs raises the question on how cellular-fate options emerge and at which stem-like stage lineage priming is initiated. Here, we investigate single-cell chromatin accessibility of Lineage-, cKit+, and Sca1+ (LSK) HSPCs spanning the early differentiation landscape. Application of a signal-processing algorithm to detect transition points corresponding to massive alterations in accessibility of 571 transcription factor motifs reveals a population of LSK FMS-like tyrosine kinase 3 (Flt3)intCD9high cells that concurrently display stem-like and lineage-affiliated chromatin signatures, pointing to a simultaneous gain of both lympho-myeloid and megakaryocyte-erythroid programs. Molecularly and functionally, these cells position between stem cells and committed progenitors and display multi-lineage capacity in vitro and in vivo but lack self-renewal activity. This integrative molecular analysis resolves the heterogeneity of cells along hematopoietic differentiation and permits investigation of chromatin-mediated transition between multipotency and lineage restriction.
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| 18. |
- Safi, Fatemeh, et al.
(författare)
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In vitro clonal multilineage differentiation of distinct murine hematopoietic progenitor populations
- 2023
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Ingår i: STAR Protocols. - : Elsevier BV. - 2666-1667. ; 4:1
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Tidskriftsartikel (refereegranskat)abstract
- Here we describe an in vitro co-culture system that can differentiate hematopoietic progenitor populations to all major hematopoietic lineages at clonal level. We present both a sensitive single-cell switch-culture system as well as a less laborious alternative barcoding protocol more convenient for larger cell numbers. Importantly, generation of all lineages from single long-term hematopoietic stem cells are described, following 21 days of culture. This protocol represents an efficient tool for validation experiments for single-cell genomics data. For complete details on the use and execution of this protocol, please refer to Safi et al. (2022).1
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| 19. |
- Sommarin, Mikael N.E., et al.
(författare)
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Single-cell multiomics of human fetal hematopoiesis define a developmental-specific population and a fetal signature
- 2023
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Ingår i: Blood Advances. - 2473-9529. ; 7:18, s. 5325-5340
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Tidskriftsartikel (refereegranskat)abstract
- Knowledge of human fetal blood development and how it differs from adult blood is highly relevant to our understanding of congenital blood and immune disorders and childhood leukemia, of which the latter can originate in utero. Blood formation occurs in waves that overlap in time and space, adding to heterogeneity, which necessitates single-cell approaches. Here, a combined single-cell immunophenotypic and transcriptional map of first trimester primitive blood development is presented. Using CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing), the molecular profile of established immunophenotype-gated progenitors was analyzed in the fetal liver (FL). Classical markers for hematopoietic stem cells (HSCs), such as CD90 and CD49F, were largely preserved, whereas CD135 (FLT3) and CD123 (IL3R) had a ubiquitous expression pattern capturing heterogenous populations. Direct molecular comparison with an adult bone marrow data set revealed that the HSC state was less frequent in FL, whereas cells with a lymphomyeloid signature were more abundant. An erythromyeloid–primed multipotent progenitor cluster was identified, potentially representing a transient, fetal-specific population. Furthermore, differentially expressed genes between fetal and adult counterparts were specifically analyzed, and a fetal core signature was identified. The core gene set could separate subgroups of acute lymphoblastic leukemia by age, suggesting that a fetal program may be partially retained in specific subgroups of pediatric leukemia. Our detailed single-cell map presented herein emphasizes molecular and immunophenotypic differences between fetal and adult blood cells, which are of significance for future studies of pediatric leukemia and blood development in general.
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| 20. |
- 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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| 21. |
- 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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