Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002874 (aplastic anemia)
 5,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The flt3 ligand is a growth factor that stimulates the proliferation of hematopoietic progenitor and stem cells. We established a sensitive enzyme-linked immunosorbent assay (ELISA) to measure the concentration of flt3 ligand in plasma or serum from normal individuals, as well as in patients with hematopoietic disorders. Concentrations of flt3 ligand in plasma or serum from normal individuals were quite low: only 12% (7 of 60) of normal individuals had flt3 ligand levels above 100 pg/mL (the limit of detection). In contrast, 86% (19 of 22) of samples from patients with Fanconi anemia and 100% (eight of eight) of samples from patients with acquired aplastic anemia had plasma or serum levels above 100 pg/mL. Mean plasma or serum concentrations (calculated by assigning a value of 0 pg/mL to any sample reading below the level of detection) were as follows: normal volunteers, 14 pg/mL; patients with Fanconi anemia, 1,331 pg/mL; and patients with acquired aplastic anemia, 460 pg/mL. Concentrations of flt3 ligand in blood are, therefore, specifically elevated to a level that may be physiologically relevant in hematopoietic disorders with a suspected stem cell component. The elevated flt3 ligand concentrations in these individuals may be part of a compensatory hematopoietic response to boost the level of progenitor cells.
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PMID:Plasma/serum levels of flt3 ligand are low in normal individuals and highly elevated in patients with Fanconi anemia and acquired aplastic anemia. 749 65

Flt3 ligand (flt3L) is a member of a small family of cytokines acting as tyrosine kinase receptor ligands that stimulate the proliferation of primitive hematopoietic progenitors in vitro. To gain insight into the physiological role of flt3L in early hematopoiesis, levels of flt3L were determined in serum of patients with multilineage bone marrow failure and related to the severity of stem cell depletion. In patients with aplastic anemia (AA) and in cancer patients with chemotherapy-induced transient suppression of hematopoiesis, flt3L fluctuated in an inverse relationship to the degree of bone marrow failure. In severe AA at diagnosis, levels of circulating soluble flt3L were highly elevated (2,653 +/- 353 pg/mL) as compared with normal blood serum values of 14 +/- 39 pg/mL. Flt3L returned to near normal levels within the first 3 months following successful bone marrow transplantation and in autologous remission induced by immunosuppressive therapy with antilymphocyte globulin (ALG; 100 +/- 31 and 183 +/- 14 pg/mL, respectively). In contrast, rejection of the graft or relapse of the disease after ALG was accompanied by an increase to high pretreatment concentrations of the circulating cytokine (3,770 +/- 2,485 and 1,788 +/- 233 pg/mL, respectively). Flt3L in serum inversely correlated with the colony-forming ability of AA bone marrow precursors in vitro (R = -.86), indicating that the concentration of the ligand reflects hematopoiesis at the progenitor cell level. Flt3L increased to 2,500 pg/mL in the serum of leukemia patients during chemoradiotherapy-induced bone marrow suppression and returned to normal values along with hematopoietic recovery. Expression of the membrane-bound form of flt3L was significantly elevated in mononuclear bone marrow and peripheral blood cells from patients with severe pancytopenia, suggesting de novo synthesis of the factor in response to bone marrow failure. The data provide a strong argument for the involvement of flt3L in the regulation of early hematopoiesis in vivo.
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PMID:Flt3 ligand level reflects hematopoietic progenitor cell function in aplastic anemia and chemotherapy-induced bone marrow aplasia. 897 41

To determine the value of flt3 ligand (flt3L) in stimulating hematopoiesis in human hypoproliferative bone marrow disorders, we examined its in vitro effect on bone marrow cells from patients with aplastic anemia (AA). Growth response to flt3L, alone and in combination with other hematopoietic growth factors, was investigated in clonogenic methylcellulose assays, in long-term liquid and stroma cultures. Bone marrow cells were derived from 13 AA patients with persisting in vitro growth defect after immunosuppressive treatment and from nine normal bone marrow donors. In methylcellulose cultures, flt3L stimulated formation of hematopoietic colonies only weakly, whereas it had an additive effect when combined with erythropoietin (Epo), stem cell factor (SCF), interleukin-3 (IL-3), interleukin-11 (IL-11), or granulocyte colony-stimulating factor (G-CSF). Flt3L was less effective than SCF and did not further enhance the number of hematopoietic colonies formed in response to SCF-containing combinations of multiple cytokines. In long-term liquid suspension cultures, flt3L was less mitogenic than SCF but its effect on the maintenance of progenitors was superior that of SCF and of IL-3, IL-11, and G-CSF. The total number of clonogenic AA cells increased as much as four-fold during the first culture week and FACS analysis demonstrated expansion of the CD34+CD38+ progenitor cell subset. Despite this enhancement, survival of AA cells remained significantly poorer than that of normal cells, in which the primitive subset of CD34+CD38- cells was maintained up to 4 weeks when flt3L was used as a single factor. Both in normal and AA cultures, flt3L promoted differentiation of cells of the myeloid lineages. In cultures of bone marrow stroma, flt3L had almost no effect on growth and survival of AA progenitors, while in cultures of normal cells the number of colony-forming cells increased up to 10-fold. Although flt3L does not overcome the proliferative defect of AA precursors, we conclude that the ligand is capable of in vitro stimulation and expansion of the reduced progenitor cell pool in AA, when used in appropriate culture conditions. The in vitro effects of flt3L on AA cells differ in many aspects from those of the structurally related cytokine SCF, suggesting a benefit in use of a combination of these two early-acting growth factors.
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PMID:Effect of flt3 ligand on in vitro growth and expansion of colony-forming bone marrow cells from patients with aplastic anemia. 921 32

The hematopoietic growth factors stem cell factor (SCF) and flt3 ligand (flt3L) are produced within the hematopoietic microenvironment in a membrane-bound and soluble isoform. To elucidate the relevance of the two isoforms in the network of early-acting cytokines, we examined the interaction of membrane-bound SCF with the soluble forms of SCF and flt3L in long-term cultures of human bone marrow cells. Feeder layers of the murine SCF-deficient Steel stromal cell line transfected with human cDNA stably expressing SCF as a transmembrane molecule were used to support growth of mononuclear cells and CD34+ progenitors derived from normal human bone marrow or from hypoplastic marrow of patients with aplastic anemia (AA). The output of nonadherent progenitor cells representing colony-forming units (CFU) and high-proliferative potential colony-forming cells (HPP-CFC) was scored weekly in secondary methylcellulose cultures; the number of colonies derived from long-term culture-initiating cells (LTC-IC) was determined in nonadherent and adherent cells at 5 weeks. Membrane-bound SCF expressed in the stromal layer was more effective than soluble SCF and soluble flt3L in maintaining clonogenic progenitors. Furthermore, the transmembrane form of SCF effectively synergized with both exogenously supplied factors, although the effect of flt3L was superior to the effect of soluble SCF. In cultures of normal bone marrow cells, addition of flt3L enhanced the total number of CFU and HPP-CFC-type progenitors, primarily of the granulocyte/macrophage lineage, by six- to ninefold after 3 weeks and of LTC-IC-derived colonies by 13-fold after 5 weeks of culture. In cultures of AA cells, both the number and the survival rate of clonogenic precursors were severely impaired even in the presence of flt3L, which, however, yielded a two- to sixfold enhancement of CFU and HPP-CFC numbers at 1 to 2 weeks. In comparison with the hematopoietic function of human Dexter-type stroma cultures, murine feeders expressing high levels of membrane-associated human SCF were equivalent in supporting hematopoiesis during the initial 3 to 4 culture weeks when supplemented with flt3L. These results demonstrate that soluble flt3L interacts with membrane-bound SCF in supporting the long-term growth of bone marrow progenitor cells. The hypothesis that SCF and flt3L function synergistically during the very early stages of human hematopoiesis is thereby reinforced.
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PMID:The membrane-bound isoform of stem cell factor synergizes with soluble flt3 ligand in supporting early hematopoietic cells in long-term cultures of normal and aplastic anemia bone marrow. 959 Jun 52

The use of hematopoietic growth factors, although well established for the management of chemotherapy-induced neutropenia, remains controversial for the treatment of aplastic anemia and inherited bone marrow failure syndromes. The most commonly used factors are granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, and erythropoietin. Newer growth factors such as stem cell factor, thrombopoietin, Flt3 ligand, and interleukins have shown promising results in the laboratory, and some have been used in clinical trials. This article reviews the clinical use of old and new hematopoietic growth factors in acquired and inherited bone marrow failure, and discusses emerging concerns about long term toxicity of these factors.
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PMID:Hematopoietic growth factors for the treatment of aplastic anemia. 966 65

Aplastic anaemia (AA) is an immune-mediated bone marrow failure associated with high serum levels of flt3 ligand (FL). We examined expression of the membrane-bound isoform of FL in peripheral blood and bone marrow cells from AA patients at diagnosis (n = 16) and after immunosuppressive (IS) treatment (n = 36). Flow cytometry demonstrated strongly increased FL levels on the cell surface of T lymphocytes in AA relative to normal controls (P < 0.0001). T-cell-specific expression of membrane-bound FL was confirmed by confocal microscopy. FL mRNA and total cellular FL protein levels were increased about threefold. Overexpression of FL in AA was observed for up to 20 years after IS treatment. FL levels correlated inversely with CD34+ cell numbers and the colony-forming ability of AA bone marrow (R = -0.68 and -0.85 respectively). Histological examination of spleen specimens and bone marrow biopsies gave no evidence of degeneration or fibrosis due to prolonged exposure to high FL. Levels of membrane-bound FL were not increased in autoimmune diseases (n = 23), including rheumatoid arthritis and lupus erythematosus, nor in graft-versus-host disease (n = 8). Chronic overexpression of FL on the surface of T lymphocytes in AA, but not in other T-cell-mediated disorders, suggests that membrane-bound FL plays a role in cell-cell interactions in bone marrow failure and may be important for long-term haemopoietic recovery.
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PMID:Chronic overexpression of membrane-bound flt3 ligand by T lymphocytes in severe aplastic anaemia. 1084 2

Flt3 ligand (FL) is a good indicator of bone marrow (BM) cellularity, having a reciprocal relationship with white blood cell (WBC) count in aplastic anemia and chemotherapy-induced neutropenia. In this report, serum FL level was measured by enzyme-linked immunosorbent assay (ELISA), in 16 consecutive patients undergoing autologous peripheral stem cell transplantation, with an average of 12 selected levels for each patient based on major changes of WBC counts at different procedure stations. We found a significant increase of serum FL level at the WBC nadir after mobilization chemotherapy and a more dramatic increase at the WBC nadir post transplantation, consistent with a more profound BM aplasia after myeloablative chemotherapy as compared to high-dose cyclophosphamide used for mobilization. Hence, we reproduced the reciprocal relationship between serum FL and BM cellularity. A direct correlation between the increase of FL level after mobilization chemotherapy and the length of mobilization was also established, which may help physicians, at the individual patient level, to predict the time of stem cell collection. Finally, we showed a direct correlation between the peripheral CD34+ count at the time of stem cell collection and the peak FL level after transplantation, which can reflect BM stromal cell function. Our results suggest that variation of serum FL level may be used as predictive indicator of hematopoietic stem cell (HSC) mobilization.
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PMID:Serum Flt3 ligand variation as a predictive indicator of hematopoietic stem cell mobilization. 1218 38