| 1. |
- Adolfsson, Jörgen, et al.
(author)
-
Identification of Flt3(+) lympho-myeloid stem cells lacking erythro-megakaryocytic potential: A revised road map for adult blood lineage commitment
- 2005
-
In: Cell. - : Elsevier (Cell Press). - 0092-8674 .- 1097-4172. ; 121:2, s. 295-306
-
Journal article (peer-reviewed)abstract
- All blood cell lineages derive from a common hematopoietic stem cell (HSC). The current model implicates that the first lineage commitment step of adult pluripotent HSCs results in a strict separation into common lymphoid and common myeloid precursors. We present evidence for a population of cells which, although sustaining a high proliferative and combined lympho-myeloid differentiation potential, have lost the ability to adopt erythroid and megakaryocyte lineage fates. Cells in the Lin-Sca-1+c-kit+ HSC compartment coexpressing high levels of the tyrosine kinase receptor Flt3 sustain granulocyte, monocyte, and B and T cell potentials but in contrast to Lin-Sca-1(+)ckit(+)Flt3(-) HSCs fail to produce significant erythroid and megakaryocytic progeny. This distinct lineage restriction site is accompanied by downregulation of genes for regulators of erythroid and megakaryocyte development. In agreement with representing a lymphoid primed progenitor, Lin(-)Sca-l(+)c-kit(+)CD34(+)Flt3(+) cells display upregulated IL-7 receptor gene expression. Based on these observations, we propose a revised road map for adult blood lineage development.
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| 2. |
- Buza-Vidas, Natalija, et al.
(author)
-
Crucial role of FLT3 ligand in immune reconstitution following bone marrow transplantation and high dose chemotherapy.
- 2007
-
In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 110:1, s. 424-432
-
Journal article (peer-reviewed)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
(author)
-
Cytokine Regulation of Hematopoietic Stem Cells and Lymphopoiesis
- 2007
-
Doctoral thesis (other academic/artistic)abstract
- Large numbers of blood cells need to be continuously replaced in order to sustain the crucial functions of the immune system, oxygen transport and blood clotting. The large diversity of cell types required to maintain the integrity of the blood system are all produced from blood forming or hematopoietic stem cells (HSCs). HSCs have the unique property of self renewal, ensuring life-long replenishment of all the blood cell types. Hematopoietic growth factors, so called cytokines, have previously been demonstrated to be important for the survival and proliferation of committed progenitor cells and development of different blood cell lineages. However, their potential role in regulating HSCs remains to a large degree unresolved. Herein, we provide data that establish the adaptor protein LNK as an important negative regulator of postnatal HSC expansion, acting as an inhibitor of the cytokine Thrombopoietin, known to be important for HSC maintenance and/or expansion. Furthermore, whereas previous studies demonstrated that another cytokine, fms-like tyrosine kinase receptor 3 (FLT3) ligand (FL), is an important regulator of B cell progenitors but has a redundant role in steady state maintenance of mature B cells, we here demonstrate that FL plays a crucial role in the regeneration of not only B cell progenitors but also mature B cells after bone marrow (BM) transplantation and chemotherapy. In addition, through studies of FL-deficient mice we show that FL plays an important role in maintaining conventional B cells with age, but is redundant in maintaining a normal compartment of fetally/postnatally derived B1 and marginal zone B cells. It has been disputed whether FL also is important in HSC regulation. Our present findings establish that FL is not important for regulating HSC maintenance or expansion neither during fetal development or in adult steady state hematopoiesis, nor following BM transplantation or chemotherapy-induced BM ablation. Finally, through identification of a multipotent progenitor in adult BM, with sustained granulocyte-monocyte and lymphocyte potential, but little or no megakaryocyte and erythroid potential, we provide evidence for a strict separation of myelopoiesis and lymphopoiesis, not being the first lineage commitment step of HSCs.
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| 4. |
- Buza-Vidas, Natalija, et al.
(author)
-
Cytokines regulate postnatal hematopoietic stem cell expansion : Opposing roles of thrombopoietin and LNK
- 2006
-
In: Genes & Development. - Woodbury, NY, USA : Cold Spring Harbor Laboratory Press (CSHL). - 0890-9369 .- 1549-5477. ; 20:15, s. 2018-2023
-
Journal article (peer-reviewed)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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| 5. |
- Buza-Vidas, Natalija, et al.
(author)
-
Delineation of the earliest lineage commitment steps of haematopoietic stem cells: new developments, controversies and major challenges
- 2007
-
In: Current Opinion in Hematology. - 1531-7048. ; 14:4, s. 315-321
-
Journal article (peer-reviewed)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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| 6. |
- Buza-Vidas, Natalija, et al.
(author)
-
FLT3 expression initiates in fully multipotent mouse hematopoietic progenitor cells
- 2011
-
In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 118:6, s. 1544-1548
-
Journal article (peer-reviewed)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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| 7. |
- Buza-Vidas, Natalija, et al.
(author)
-
FLT3 receptor and ligand are dispensable for maintenance and posttransplantation expansion of mouse hematopoietic stem cells
- 2009
-
In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 113:15, s. 3453-3460
-
Journal article (peer-reviewed)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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| 8. |
- Böiers, Charlotta, et al.
(author)
-
Expression and role of FLT3 in regulation of the earliest stage of normal granulocyte-monocyte progenitor development.
- 2010
-
In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; May 4, s. 5061-5068
-
Journal article (peer-reviewed)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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| 9. |
- Drissen, Roy, et al.
(author)
-
Distinct myeloid progenitor-differentiation pathways identified through single-cell RNA sequencing
- 2016
-
In: Nature Immunology. - : Springer Science and Business Media LLC. - 1529-2908 .- 1529-2916. ; 17:6, s. 666-676
-
Journal article (peer-reviewed)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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| 10. |
- Kharazi, Shabnam, et al.
(author)
-
Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD-induced myeloproliferation
- 2011
-
In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 118:13, s. 3613-3621
-
Journal article (peer-reviewed)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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| 11. |
- Lee, Benjamin H., et al.
(author)
-
FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia
- 2007
-
In: Cancer Cell. - : Elsevier BV. - 1878-3686 .- 1535-6108. ; 12:4, s. 367-380
-
Journal article (peer-reviewed)abstract
- Despite their known transforming properties, the effects of leukemogenic FLT3-ITD mutations on hematopoietic stem and multipotent progenitor cells and on hematopoietic differentiation are not well understood. We report a mouse model harboring an ITD in the murine Flt3 locus that develops myeloproliferative disease resembling CMML and further identified FLT3-ITD mutations in a subset of human CMML. These findings correlated with an increase in number, cell cycling, and survival of multipotent stem and progenitor cells in an ITD dose-dependent manner in animals that exhibited alterations within their myeloid progenitor compartments and a block in normal B cell development. This model provides insights into the consequences of constitutive signaling by an oncogenic tyrosine kinase on hematopoietic progenitor quiescence, function, and cell fate.
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| 12. |
- Luc, Sidinh, et al.
(author)
-
Biological and molecular evidence for existence of lymphoid-primed multipotent progenitors
- 2007
-
In: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923. ; 1106, s. 89-94
-
Journal article (peer-reviewed)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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| 13. |
- Luc, Sidinh, et al.
(author)
-
Delineating the cellular pathways of hematopoietic lineage commitment.
- 2008
-
In: Seminars in Immunology. - : Elsevier BV. - 1096-3618 .- 1044-5323. ; 20, s. 213-220
-
Journal article (peer-reviewed)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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| 14. |
- Luc, Sidinh, et al.
(author)
-
Downregulation of Mpl marks the transition to lymphoid-primed multipotent progenitors with gradual loss of granulocyte-monocyte potential.
- 2008
-
In: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 111:7, s. 3424-3434
-
Journal article (peer-reviewed)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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| 15. |
- Luc, Sidinh, et al.
(author)
-
The earliest thymic T cell progenitors sustain B cell and myeloid lineage potential.
- 2012
-
In: Nature Immunology. - : Springer Science and Business Media LLC. - 1529-2908 .- 1529-2916. ; 13:4, s. 412-419
-
Journal article (peer-reviewed)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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| 16. |
- Mead, Adam J., et al.
(author)
-
FLT3-ITDs Instruct a Myeloid Differentiation and Transformation Bias in Lymphomyeloid Multipotent Progenitors
- 2013
-
In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 3:6, s. 1766-1776
-
Journal article (peer-reviewed)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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| 17. |
- Månsson, Robert, et al.
(author)
-
Molecular evidence for hierarchical transcriptional lineage priming in fetal and adult stem cells and multipotent progenitors
- 2007
-
In: Immunity. - : Elsevier BV. - 1074-7613 .- 1097-4180. ; 26:4, s. 407-419
-
Journal article (peer-reviewed)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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| 18. |
- Qian, Hong, et al.
(author)
-
Critical role of thrombopoietin in maintaining adult quiescent hematopoietic stem cells.
- 2007
-
In: Cell Stem Cell. - : Elsevier BV. - 1934-5909. ; 1:6, s. 671-684
-
Journal article (peer-reviewed)abstract
- The role of cytokines in regulation of hematopoietic stem cells (HSCs) remains poorly understood. Herein we demonstrate that thrombopoietin (THPO) and its receptor, MPL, are critically involved in postnatal steady-state HSC maintenance, reflected in a 150-fold reduction of HSCs in adult Thpo(-/-) mice. Further, whereas THPO and MPL proved not required for fetal HSC expansion, HSC expansion posttransplantation was highly MPL and THPO dependent. The distinct role of THPO in postnatal HSC maintenance is accompanied by accelerated HSC cell-cycle kinetics in Thpo(-/-) mice and reduced expression of the cyclin-dependent kinase inhibitors p57(Kip2) and p19(INK4D) as well as multiple Hox transcription factors. Although also predicted to be an HSC viability factor, BCL2 failed to rescue the HSC deficiency of Thpo(-/-) mice. Thus, THPO regulates posttransplantation HSC expansion as well as the maintenance of adult quiescent HSCs, of critical importance to avoid postnatal HSC exhaustion.
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| 19. |
- Sitnicka Quinn, Ewa, et al.
(author)
-
Complementary Signaling through flt3 and Interleukin-7 Receptor {alpha} Is Indispensable for Fetal and Adult B Cell Genesis.
- 2003
-
In: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 198:10, s. 1495-1506
-
Journal article (peer-reviewed)abstract
- Extensive studies of mice deficient in one or several cytokine receptors have failed to support an indispensable role of cytokines in development of multiple blood cell lineages. Whereas B1 B cells and Igs are sustained at normal levels throughout life of mice deficient in IL-7, IL-7R{alpha}, common cytokine receptor gamma chain, or flt3 ligand (FL), we report here that adult mice double deficient in IL-7R{alpha} and FL completely lack visible LNs, conventional IgM+ B cells, IgA+ plasma cells, and B1 cells, and consequently produce no Igs. All stages of committed B cell progenitors are undetectable in FL-/- x IL-7R{alpha}-/- BM that also lacks expression of the B cell commitment factor Pax5 and its direct target genes. Furthermore, in contrast to IL-7R{alpha}-/- mice, FL-/- x IL-7R{alpha}-/- mice also lack mature B cells and detectable committed B cell progenitors during fetal development. Thus, signaling through the cytokine tyrosine kinase receptor flt3 and IL-7R{alpha} are indispensable for fetal and adult B cell development.
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| 20. |
- Sitnicka Quinn, Ewa, et al.
(author)
-
Critical role of FLT3 ligand in IL-7 receptor-independent T lymphopoiesis and regulation of lymphoid-primed multipotent progenitors
- 2007
-
In: Blood. - Washington, DC : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 110:8, s. 2955-2964
-
Journal article (peer-reviewed)abstract
- The molecular pathways regulating lymphoid priming, fate, and development of multipotent bone marrow (BM) stem/progenitor cells that continuously replace thymic progenitors remain largely unknown. Herein, we show that fms-like tyrosine kinase 3 (Flt3) ligand (Fl)-deficient mice have distinct reductions in the earliest thymic progenitors in fetal, postnatal, and adult thymus. A critical role of FL in thymopoiesis was particularly evident in the absence of interleukin-7 receptor alpha (IL-7Ralpha) signaling. Fl-/-Il-7r-/- mice have extensive reductions in fetal and postnatal thymic progenitors that result in a loss of active thymopoiesis in adult mice, demonstrating an indispensable role of FL in IL-7Ralpha-independent fetal and adult T lymphopoiesis. Moreover, we establish a unique and critical role of FL, distinct from that of IL-7Ralpha, in regulation of the earliest lineage-negative (Lin(-)) Lin(-)SCA1+KIT+ (LSK) FLT3(hi) lymphoid-primed multipotent progenitors in BM, demonstrating a key role of FLT3 signaling in regulating the very earliest stages of lymphoid progenitors.
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| 21. |
- Sitnicka Quinn, Ewa, et al.
(author)
-
Human CD34+ hematopoietic stem cells capable of multilineage engrafting NOD/SCID mice express flt3 : Distinct flt3 and c-kit expression and response patterns on mouse and candidate human hematopoietic stem cells
- 2003
-
In: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 102:3, s. 881-886
-
Journal article (peer-reviewed)abstract
- The cytokine tyrosine kinase receptors c-kit and flt3 are expressed and function in early mouse and human hematopoiesis. Through its ability to promote ex vivo expansion and oncoretroviral transduction of primitive human hematopoietic progenitors, the flt3 ligand (FL) has emerged as a key stimulator of candidate human hematopoietic stem cells (HSCs). However, recent studies in the mouse suggest that though it is present on short-term repopulating cells, flt3 is not expressed on bone marrow long-term reconstituting HSCs, the ultimate target for the development of cell replacement and gene therapy. Herein we demonstrate that though only a fraction of human adult bone marrow and cord blood CD34+long-term culture-initiating cells (LTC-ICs) express flt3, most cord blood lymphomyeloid HSCs capable of in vivo reconstituting nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice are flt3+. The striking difference in flt3 and c-kit expression on mouse and candidate human HSCs translated into a corresponding difference in flt3 and c-kit function because FL was more efficient than SCF at supporting the survival of candidate human HSCs. In contrast, SCF is far superior to FL as a viability factor for mouse HSCs. Thus, the present data provide compelling evidence for a contrasting expression and response pattern of flt3 and c-kit on mouse and human HSCs.
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| 22. |
- Sitnicka Quinn, Ewa, et al.
(author)
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Key Role of flt3 Ligand in Regulation of the Common Lymphoid Progenitor but Not in Maintenance of the Hematopoietic Stem Cell Pool.
- 2002
-
In: Immunity. - 1074-7613. ; 17:4, s. 463-472
-
Journal article (peer-reviewed)abstract
- The first lineage commitment step of hematopoietic stem cells (HSC) results in separation into distinct lymphoid and myeloid differentiation pathways, reflected in the generation of common lymphoid and myeloid progenitors (CLP and CMP, respectively). In this report we present the first evidence for a nonredundant regulator of this process, in that adult mice deficient in expression of the flt3 ligand (FL) have severely (10-fold) reduced levels of the CLP, accompanied by reductions in the earliest identifiable B and T cell progenitors. In contrast, CMP and HSC are unaffected in FL-deficient mice. Noteworthy, CLP express high levels of both the flt3 receptor and ligand, indicating a potential autocrine role of FL in regulation of the earliest lymphoid commitment step from HSC.
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| 23. |
- Tehranchi, Ramin, et al.
(author)
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Persistent malignant stem cells in del(5q) myelodysplasia in remission.
- 2010
-
In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 363:11, s. 1025-1037
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Journal article (peer-reviewed)abstract
- BACKGROUND: The in vivo clinical significance of malignant stem cells remains unclear. METHODS: Patients who have the 5q deletion (del[5q]) myelodysplastic syndrome (interstitial deletions involving the long arm of chromosome 5) have complete clinical and cytogenetic remissions in response to lenalidomide treatment, but they often have relapse. To determine whether the persistence of rare but distinct malignant stem cells accounts for such relapses, we examined bone marrow specimens obtained from seven patients with the del(5q) myelodysplastic syndrome who became transfusion-independent while receiving lenalidomide treatment and entered cytogenetic remission. RESULTS: Virtually all CD34+, CD38+ progenitor cells and stem cells that were positive for CD34 and CD90, with undetectable or low CD38 (CD38−/low), had the 5q deletion before treatment. Although lenalidomide efficiently reduced these progenitors in patients in complete remission, a larger fraction of the minor, quiescent, CD34+,CD38-/low, CD90+ del(5q) stem cells as well as functionally defined del(5q) stem cells remained distinctly resistant to lenalidomide. Over time, lenalidomide resistance developed in most of the patients in partial and complete remission, with recurrence or expansion of the del(5q) clone and clinical and cytogenetic progression. CONCLUSIONS: In these patients with the del(5q) myelodysplastic syndrome, we identified rare and phenotypically distinct del(5q) myelodysplastic syndrome stem cells that were also selectively resistant to therapeutic targeting at the time of complete clinical and cytogenetic remission. (Funded by the EuroCancerStemCell Consortium and others.)
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