| 1. |
- Woll, Petter S, et al.
(författare)
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Myelodysplastic Syndromes Are Propagated by Rare and Distinct Human Cancer Stem Cells In Vivo.
- 2014
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Ingår i: Cancer Cell. - : Elsevier BV. - 1878-3686 .- 1535-6108. ; 25:6, s. 794-808
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Tidskriftsartikel (refereegranskat)abstract
- Evidence for distinct human cancer stem cells (CSCs) remains contentious and the degree to which different cancer cells contribute to propagating malignancies in patients remains unexplored. In low- to intermediate-risk myelodysplastic syndromes (MDS), we establish the existence of rare multipotent MDS stem cells (MDS-SCs), and their hierarchical relationship to lineage-restricted MDS progenitors. All identified somatically acquired genetic lesions were backtracked to distinct MDS-SCs, establishing their distinct MDS-propagating function in vivo. In isolated del(5q)-MDS, acquisition of del(5q) preceded diverse recurrent driver mutations. Sequential analysis in del(5q)-MDS revealed genetic evolution in MDS-SCs and MDS-progenitors prior to leukemic transformation. These findings provide definitive evidence for rare human MDS-SCs in vivo, with extensive implications for the targeting of the cells required and sufficient for MDS-propagation.
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| 2. |
- Buza-Vidas, Natalija, et al.
(författare)
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Crucial role of FLT3 ligand in immune reconstitution following bone marrow transplantation and high dose chemotherapy.
- 2007
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 110:1, s. 424-432
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Tidskriftsartikel (refereegranskat)abstract
- Almost 5 decades after the first clinical transplantations, delayed immune reconstitution remains a considerable hurdle in bone marrow transplantation, and the mechanisms regulating immune reconstitution after transplantation remain to be established. Whereas adult fms-like tyrosine kinase 3 ligand-deficient (FL-/-) mice have reduced numbers of early Band T-cell progenitors, they sustain close to normal levels of mature B and T cells. Herein, we demonstrate that adult bone marrow cells fail to reconstitute B-cell progenitors and conventional B cells in lethally irradiated FL-/- recipients, which also display delayed kinetics of T-cell reconstitution. Similarly, FL is essential for B-cell regeneration after chemotherapy-induced myeloablation. In contrast, fetal progenitors reconstitute B lymphopoiesis in FL-/- mice, albeit at reduced levels. A critical role of FL in adult B lymphopoiesis is further substantiated by an age-progressive decline in peripheral conventional B cells in FL-/- mice, whereas fetally and early postnatally derived B1 and marginal zone B cells are sustained in a FL-independent manner. Thus, FL plays a crucial role in sustaining conventional B lymphopoiesis in adult mice and, as a consequence, our findings implicate a critical role of FL in promoting immune reconstitution after myeloablation and bone marrow transplantation.
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| 3. |
- 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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| 4. |
- Buza-Vidas, Natalija, et al.
(författare)
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FLT3 receptor and ligand are dispensable for maintenance and posttransplantation expansion of mouse hematopoietic stem cells
- 2009
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 113:15, s. 3453-3460
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Tidskriftsartikel (refereegranskat)abstract
- Originally cloned from hematopoietic stem cell (HSC) populations and its ligand being extensively used to promote ex vivo HSC expansion, the FMS-like tyrosine kinase 3 (FLT3; also called FLK2) receptor and its ligand (FL) were expected to emerge as an important physiologic regulator of HSC maintenance and expansion. However, the role of FLT3 receptor and ligand in HSC regulation remains unclear and disputed. Herein, using Fl-deficient mice, we establish for the first time that HSC expansion in fetal liver and after transplantation is FL independent. Because previous findings in Flk2(-/-) mice were compatible with an important role of FLT3 receptor in HSC regulation and because alternative ligands might potentially interact directly or indirectly with FLT3 receptor, we here also characterized HSCs in Flk2(-/-) mice. Advanced phenotypic as well as functional evaluation of Flk2(-/-) HSCs showed that the FLT3 receptor is dispensable for HSC steady-state maintenance and expansion after transplantation. Taken together, these studies show that the FLT3 receptor and ligand are not critical regulators of mouse HSCs, neither in steady state nor during fetal or posttransplantation expansion. (Blood. 2009; 113: 3453-3460)
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| 5. |
- 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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