| 1. |
- Bereshchenko, Oxana, et al.
(författare)
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Hematopoietic Stem Cell Expansion Precedes the Generation of Committed Myeloid Leukemia-initiating Cells in C/EBP alpha Mutant AML
- 2009
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Ingår i: Cancer Cell. - : Elsevier BV. - 1878-3686 .- 1535-6108. ; 16:5, s. 390-400
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Tidskriftsartikel (refereegranskat)abstract
- We here use knockin mutagenesis in the mouse to model the spectrum of acquired CEBPA mutations in human acute myeloid leukemia. We find that C-terminal C/EBP alpha mutations increase the proliferation of long-term hematopoietic stem cells (LT-HSCs) in a cell-intrinsic manner and override normal HSC homeostasis, leading to expansion of premalignant HSCs. However, such mutations impair myeloid programming of HSCs and block myeloid lineage commitment when homozygous. In contrast, N-terminal C/EBP alpha mutations are silent with regards to HSC expansion, but allow the formation of committed myeloid progenitors, the templates for leukemia-initiating cells. The combination of N- and C-terminal C/EBP alpha mutations incorporates both features, accelerating disease development and explaining the clinical prevalence of this configuration of CEBPA mutations.
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| 2. |
- Buza-Vidas, Natalija, et al.
(författare)
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Cytokines regulate postnatal hematopoietic stem cell expansion : Opposing roles of thrombopoietin and LNK
- 2006
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Ingår i: Genes & Development. - Woodbury, NY, USA : Cold Spring Harbor Laboratory Press (CSHL). - 0890-9369 .- 1549-5477. ; 20:15, s. 2018-2023
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Tidskriftsartikel (refereegranskat)abstract
- The role of cytokines as regulators of hematopoietic stem cell (HSC) expansion remains elusive. Herein, we identify thrombopoietin (THPO) and the cytokine signaling inhibitor LNK, as opposing physiological regulators of HSC expansion. Lnk(-/-) HSCs continue to expand postnatally, up to 24-fold above normal by 6 mo of age. Within the stem cell compartment, this expansion is highly selective for self-renewing long-term HSCs (LT-HSCs), which show enhanced THPO responsiveness. Lnk(-/-) HSC expansion is dependent on THPO, and 12-wk-old Lnk(-/-)Thpo(-/-) mice have 65-fold fewer LT-HSCs than Lnk(-/-) mice. Expansions of multiple myeloid, but not lymphoid, progenitors in Lnk(-/-) mice also proved THPO-dependent.
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| 3. |
- Buza-Vidas, Natalija, et al.
(författare)
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Delineation of the earliest lineage commitment steps of haematopoietic stem cells: new developments, controversies and major challenges
- 2007
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Ingår i: Current Opinion in Hematology. - 1531-7048. ; 14:4, s. 315-321
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Tidskriftsartikel (refereegranskat)abstract
- Purpose of review This review addresses recently reported evidence for alternative cellular pathways for haematopoietic stem cell lineage commitment. Recent findings Using various approaches, several laboratories suggested the existence of adult as well as foetal multipotent progenitor cells with combined B cell, T cell and granulocyte/macrophage potential, but little or no megakaryocyte/erythroid potential. Compared with haematopoietic stem cells, these multipotent progenitor cells exhibited downregulated transcriptional expression of genes of the megakaryocyte/erythroid lineages and upregulated expression of lymphoid lineage genes. The existence of these lineage-restricted multipotent progenitor cells suggests that the first lineage commitment step of haematopoietic stem cells does not result in strict separation into myelopoiesis and lymphopoiesis, and that there might be alternative pathways for commitment toward different lineage fates. These findings have been questioned by other studies, however. To resolve this controversy and establish the complete road map for haematopoietic lineage commitment, improved tools and more stringent standards for how to identify and characterize lineage fate options of distinct stem and progenitor cells are needed. Summary Current and future progress in establishing the complete cellular roadmap for haematopoietic lineage commitment will permit identification and characterization of key regulators of lineage fate decisions in haematopoietic stem cells.
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| 4. |
- Buza-Vidas, Natalija, et al.
(författare)
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FLT3 expression initiates in fully multipotent mouse hematopoietic progenitor cells
- 2011
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 118:6, s. 1544-1548
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Tidskriftsartikel (refereegranskat)abstract
- Lymphoid-primed multipotent progenitors with down-regulated megakaryocyte-erythroid (MkE) potential are restricted to cells with high levels of cell-surface FLT3 expression, whereas HSCs and MkE progenitors lack detectable cell-surface FLT3. These findings are compatible with FLT3 cell-surface expression not being detectable in the fully multipotent stem/progenitor cell compartment in mice. If so, this process could be distinct from human hematopoiesis, in which FLT3 already is expressed in multipotent stem/progenitor cells. The expression pattern of Flt3 (mRNA) and FLT3 (protein) in multipotent progenitors is of considerable relevance for mouse models in which prognostically important Flt3 mutations are expressed under control of the endogenous mouse Flt3 promoter. Herein, we demonstrate that mouse Flt3 expression initiates in fully multipotent progenitors because in addition to lymphoid and granulocyte-monocyte progenitors, FLT3(-) Mk- and E-restricted downstream progenitors are also highly labeled when Flt3-Cre fate mapping is applied. (Blood. 2011;118(6):1544-1548)
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| 5. |
- 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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| 6. |
- 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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| 7. |
- Luc, Sidinh, et al.
(författare)
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Biological and molecular evidence for existence of lymphoid-primed multipotent progenitors
- 2007
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923. ; 1106, s. 89-94
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Tidskriftsartikel (refereegranskat)abstract
- Studies from our and other laboratories have over the last 2 years implicated the existence of multipotent progenitors (MPPs) with combined granulocyte-macrophage, B cell, and T cell potential, but little or no megakaryocyte-erythroid (MkE) potential in the adult bone marrow Lineage (-)SCA-1 +KIT+ (LSK) compartment of multipotent stem and progenitor cells. The evidence for the existence of LSKCD34(+) FLT3(hi) lymphoid-primed MPPs (LMPPs) implicates that a strict separation into common myeloid and lymphoid pathways might not be the first lineage commitment step of hematopoietic stem cells (HSCs). Together with the evidence for existence of common myeloid and common lymphoid progenitors (CMPs and CLPs, respectively), the identification of LMPPs also suggests that at least the granulocyte-macrophage lineage can be generated through alternative pathways. However, the existence of LMPPs has recently been questioned, as there is evidence that at least a fraction of LSKCD34(+) FLT3(hi) cells sustains MkE potential. Thus, in more recent studies we have in more detail compared the molecular signature of adult LMPPs to populations of LSK cells enriched for cells with pluripotent HSC activity. Notably, we have found at the global as well as single-cell level that LMPPs when compared with pluripotent HSCs downregulate the transcriptional priming of genes typically expressed in cells of the MkE lineage, while upregulating early lymphoid genes. Although other studies have suggested that the earliest HSC commitment steps might differ in fetal and adult hematopoiesis, we have also obtained evidence suggesting that the LMPP is defined already during fetal development.
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| 8. |
- Luc, Sidinh, et al.
(författare)
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Delineating the cellular pathways of hematopoietic lineage commitment.
- 2008
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Ingår i: Seminars in Immunology. - : Elsevier BV. - 1096-3618 .- 1044-5323. ; 20, s. 213-220
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Tidskriftsartikel (refereegranskat)abstract
- The prevailing model for adult hematopoiesis postulates that the first lineage commitment step results in a strict separation of common myeloid and common lymphoid pathways. However, the recent identification of granulocyte/monocyte (GM)-lymphoid restricted lymphoid-primed multipotent progenitors (LMPPs) and primitive common myeloid progenitors (CMPs) within the "HSC" compartment provide compelling support for establishment of independent GM-megakaryocyte/erythroid (GM-MkE) and GM-lymphoid commitment pathways as decisive early lineage fate decisions. These changes in lineage potentials are corroborated by corresponding changes in multilineage transcriptional priming, as LMPPs down-regulate MkE priming but become GM-lymphoid transcriptionally primed, whereas CMPs are GM-MkE primed. These distinct biological and molecular relationships are established already in the fetal liver.
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| 9. |
- 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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| 10. |
- Luc, Sidinh
(författare)
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Lineage commitment to a T
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- he hematopoietic development is a highly dynamic but tightly regulated process. The flexibility to produce blood cells through more than one route will allow the blood system to respond rapidly in stress situations such as infections. On the other hand, regulation of the blood system is required to prevent blood cells from uncontrolled proliferation that could result in leukemia or bone marrow failure due to depletion of blood cells. Hematopoietic stem cells are cells that can differentiate to all blood lineages and maintain the whole hematopoietic system throughout a lifetime. This differentiation process through which stem cells generate mature blood cells occurs through different lineage commitment steps. The precise mapping of the lineage commitment events in normal hematopoietic development is essential to understand its regulation and also to unravel the underlying mechanisms in various hematological diseases. The aim of my thesis has been to study and delineate early lineage commitment processes in the hematopoietic stem cell compartment and in lymphopoiesis with a particular emphasis on T cell development in adult and fetal hematopoiesis using the mouse as a model system. In the thesis I present studies that support an alternative lineage commitment model to the classical and prevailing one for hematopoietic development. In the alternative model hematopoietic stem cells generate progenitors with lymphoid/myeloid (granulocyte/monocyte) and megakaryocyte/erythrocyte/myeloid fates as a first step in their lineage commitment. As the progenitors go through the differentiation to become T cells, they do not commit to a final T cell fate until they have reached and entered their final destination, the thymus. In my studies we demonstrate that the progenitor that initially seeds the thymus during early embryonic development and replenishes the thymus postnatally is more multipotent than previously appreciated. This model has not only identified new and critical commitment steps but also provides a better candidate target cell for the origin of biphenotypic leukemia, which is characterized by lymphoid and myeloid phenotypes.
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| 11. |
- Luc, Sidinh, et al.
(författare)
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The earliest thymic T cell progenitors sustain B cell and myeloid lineage potential.
- 2012
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Ingår i: Nature Immunology. - : Springer Science and Business Media LLC. - 1529-2908 .- 1529-2916. ; 13:4, s. 412-419
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Tidskriftsartikel (refereegranskat)abstract
- The stepwise commitment from hematopoietic stem cells in the bone marrow to T lymphocyte-restricted progenitors in the thymus represents a paradigm for understanding the requirement for distinct extrinsic cues during different stages of lineage restriction from multipotent to lineage-restricted progenitors. However, the commitment stage at which progenitors migrate from the bone marrow to the thymus remains unclear. Here we provide functional and molecular evidence at the single-cell level that the earliest progenitors in the neonatal thymus had combined granulocyte-monocyte, T lymphocyte and B lymphocyte lineage potential but not megakaryocyte-erythroid lineage potential. These potentials were identical to those of candidate thymus-seeding progenitors in the bone marrow, which were closely related at the molecular level. Our findings establish the distinct lineage-restriction stage at which the T cell lineage-commitment process transits from the bone marrow to the remote thymus.
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| 12. |
- 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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| 13. |
- Mead, Adam J., et al.
(författare)
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FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent Progenitors
- 2013
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 3:6, s. 1766-1776
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Tidskriftsartikel (refereegranskat)abstract
- Whether signals mediated via growth factor receptors (GFRs) might influence lineage fate in multipotent progenitors (MPPs) is unclear. We explored this issue in a mouse knockin model of gain-of-function Flt3-ITD mutation because FLT3-ITDs are paradoxically restricted to acute myeloid leukemia even though Flt3 primarily promotes lymphoid development during normal hematopoiesis. When expressed in MPPs, Flt3-ITD collaborated with Runx1 mutation to induce high-penetrance aggressive leukemias that were exclusively of the myeloid phenotype. Flt3-ITDs preferentially expanded MPPs with reduced lymphoid and increased myeloid transcriptional priming while compromising early B and T lymphopoiesis. Flt3-ITD-induced myeloid lineage bias involved upregulation of the transcription factor Pu.1, which is a direct target gene of Stat3, an aberrantly activated target of Flt3-ITDs, further establishing how lineage bias can be inflicted on MPPs through aberrant GFR signaling. Collectively, these findings provide new insights into how oncogenic mutations might subvert the normal process of lineage commitment and dictate the phenotype of resulting malignancies.
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| 14. |
- Månsson, Robert, et al.
(författare)
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Molecular evidence for hierarchical transcriptional lineage priming in fetal and adult stem cells and multipotent progenitors
- 2007
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Ingår i: Immunity. - : Elsevier BV. - 1074-7613 .- 1097-4180. ; 26:4, s. 407-419
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies implicated the existence of adult lymphoid-primed multipotent progenitors (LMPPs) with little or no megakaryocyte-erythroid potential, questioning common myeloid and lymphoid progenitors as obligate intermediates in hematopoietic stem cell (HSC) lineage commitment. However, the existence of LMPPs remains contentious. Herein, global and single-cell analyses revealed a hierarchical organization of transcriptional lineage programs, with downregulation of megakaryocyte-erythroid genes from HSCs to LMPPs, sustained granulocyte-monocyte priming, and upregulation of common lymphoid (but not B and T cell-specific) genes. These biological and molecular relationships, implicating almost mutual exclusion of megakaryocyte-erythroid and lymphoid pathways, are established already in fetal hematopoiesis, as evidenced by existence of LMPPs in fetal liver. The identification of LMPPs and hierarchically ordered transcriptional activation and downregulation of distinct lineage programs is compatible with a model for HSC lineage commitment in which the probability for undergoing different lineage commitment fates changes gradually when progressing from HSCs to LMPPs.
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| 15. |
- Pena-Perez, Lucia, et al.
(författare)
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FOXO Dictates Initiation of B Cell Development and Myeloid Restriction in Common Lymphoid Progenitors
- 2022
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Ingår i: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- The development of B cells relies on an intricate network of transcription factors critical for developmental progression and lineage commitment. In the B cell developmental trajectory, a temporal switch from predominant Foxo3 to Foxo1 expression occurs at the CLP stage. Utilizing VAV-iCre mediated conditional deletion, we found that the loss of FOXO3 impaired B cell development from LMPP down to B cell precursors, while the loss of FOXO1 impaired B cell commitment and resulted in a complete developmental block at the CD25 negative proB cell stage. Strikingly, the combined loss of FOXO1 and FOXO3 resulted in the failure to restrict the myeloid potential of CLPs and the complete loss of the B cell lineage. This is underpinned by the failure to enforce the early B-lineage gene regulatory circuitry upon a predominantly pre-established open chromatin landscape. Altogether, this demonstrates that FOXO3 and FOXO1 cooperatively govern early lineage restriction and initiation of B-lineage commitment in CLPs.
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| 16. |
- Somuncular, Ece, et al.
(författare)
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CD49b identifies functionally and epigenetically distinct subsets of lineage-biased hematopoietic stem cells
- 2022
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Ingår i: Stem Cell Reports. - : Elsevier. - 2213-6711. ; 17:7, s. 1546-1560
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Tidskriftsartikel (refereegranskat)abstract
- Hematopoiesis is maintained by functionally diverse lineage-biased hematopoietic stem cells (HSCs). The functional significance of HSC heterogeneity and the regulatory mechanisms underlying lineage bias are not well understood. However, absolute purification of HSC subtypes with a pre-determined behavior remains challenging, highlighting the importance of continued efforts toward prospective isolation of homogeneous HSC subsets. In this study, we demonstrate that CD49b subdivides the most primitive HSC compartment into functionally distinct subtypes: CD49b(-) HSCs are highly enriched for myeloid-biased and the most durable cells, while CD49b(+) HSCs are enriched for multipotent cells with lymphoid bias and reduced self-renewal ability. We further demonstrate considerable transcriptional similarities between CD49b(-) and CD49b(+) HSCs but distinct differences in chromatin accessibility. Our studies highlight the diversity of HSC functional behaviors and provide insights into the molecular regulation of HSC heterogeneity through transcriptional and epigenetic mechanisms.
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