Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several cytokines stimulating hematopoiesis, mainly lineage restricted, are already widely used in supportive care to correct myelosuppression or anaemia (GM-CSF, G-CSF, EPO). The new growth factor are tested in preclinical or clinical studies to abrogate other anti-cancer therapy side-effects (thrombocytopenia, mucositis etc.). IL-3 has been shown to have only limited effect on neutrophils and platelets production respectively. IL-6 and IL-11 have been tested to improve thrombocytopenia and mucositis (IL-11). Thrombopoetin (TPO, c-mpl) is tested in clinical trials and shows very strong effect on platelet counts. Stem cell factor (SCF) has shown to improve progenitor cell mobilisation, particularly in combination with other cytokines. The new promising factor, FLT-3 ligand, combines effect on hematopoiesis with effect on dendritic cells generation. The new group of synthetic cytokines (daniplestim, myelopoetin, promegapoetin and progenipoetin) is now tested in preclinical and clinical studies. Mucositis could be influenced by new keratinocyte growth factor (KGF), which is now in phase I trials.
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PMID:[New cytokines and their role in supportive care]. 1104 87

The first case of B-cell lymphoma of brain in a patient with myelodysplastic syndrome (MDS) was reported. A 68-year-old man was admitted because of anemia, fever, and thrombocytopenia and was diagnosed as having MDS (refractory anemia with excess of blasts) on the basis of the findings of bone marrow aspiration and chromosomal analysis. The patient was followed up without chemotherapy, but a brain tumor appeared after 3 years. Histologic and immunohistologic examinations revealed diffuse large B-cell lymphoma. Mutations of the c-kit proto-oncogene (stem cell factor receptor) and the p53 tumor-suppressor gene were examined in the MDS lesion and malignant lymphoma (ML) by the polymerase chain reaction-single-strand conformational polymorphism (PCR-SSCP) method followed by direct sequencing. The p53 mutation was not found in either MDS or ML, but a nonsense mutation (Try-557 --> stop) in exon 11 of the c-kit, which might lead to dysfunction of tyrosine kinase activity, was detected in MDS. This is the first report of c-kit mutation in MDS. Epstein-Barr virus (EBV) genome was demonstrated in the nucleus of brain ML cells by in situ hybridization with EBV-encoded RNA-1 probe. Immunohistochemistry showed that the tumor cells expressed latent infection gene products, including EBV nuclear antigen-2 and latent membrane protein-1. This pattern of latent gene expression was Lat III, which is usually found in malignant lymphomas developing in immunocompromised hosts. These findings suggest that a profound pancytopenia in MDS resulted in an immunodeficient condition, after which EBV-positive B-cell lymphoma of brain developed.
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PMID:Epstein-Barr virus associated B-cell lymphoma of brain developing in myelodysplastic syndrome with c-kit mutation (Try-557 -->stop). 1107 41

The hematopoietic stem cell has long been considered an ideal target for the introduction of therapeutic genes to treat human disorders such as Fanconi anemia (FA). Although recent progress in large animal models is encouraging, application to nonmalignant conditions is limited by the perceived necessity of myeloablative conditioning. We and others have shown that very low irradiation doses are sufficient to allow significant hematopoietic engraftment in murine hosts even after the introduction of xenogeneic genes. To determine the degree of engraftment of genetically modified cells attainable with very low irradiation doses in larger animals, we employed the rhesus macaque competitive repopulation model. Four animals underwent mobilization with stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) followed by apheresis. The apheresis product was enriched for the CD34-positive fraction by immunomagnetic selection and split equally for transduction with either G1FC26, a retroviral vector carrying the Fanconi anemia complementation group C gene, or PLII, a nonexpression control retroviral vector carrying both neomycin and beta-galactosidase gene sequences modified to prevent translation. Transductions were performed daily in the presence of fresh IL-3, IL-6, SCF, and Flt-3 ligand on fibronectin-coated plates over 96 h. Animals were conditioned with a single dose of either 100 (n = 2) or 200 (n = 2) cGy and received the combined products of transduction on the following day. None of the animals experienced clinically significant neutropenia nor required the use of central line placement, transfusional support with blood products, or intravenous antibiotics. Using real-time PCR, circulating levels of genetically modified cells as high as 1% were initially detected. Stable, albeit, significantly lower levels from both vector-transduced aliquots (<0.1%) persisted beyond 12 months posttransplant in all four animals. Although not sufficient to correct the phenotype in many human disorders, stable low-level engraftment by genetically modified cells following low-intensity conditioning may prove adequate in disorders such as FA due to the selective advantage conferred upon corrected cells.
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PMID:Persistent low-level engraftment of rhesus peripheral blood progenitor cells transduced with the fanconi anemia C gene after conditioning with low-dose irradiation. 1140 5

Fanconi anemia (FA) is a rare autosomal recessive disease, characterized by bone marrow failure and cancer predisposition. So far, 8 complementation groups have been identified, although mutations in FANCA account for the disease in the majority of FA patients. In this study we characterized the hematopoietic phenotype of a Fanca knockout mouse model and corrected the main phenotypic characteristics of the bone marrow (BM) progenitors using retroviral vectors. The hematopoiesis of these animals was characterized by a modest though significant thrombocytopenia, consistent with reduced numbers of BM megakaryocyte progenitors. As observed in other FA models, the hematopoietic progenitors from Fanca(-/-) mice were highly sensitive to mitomycin C (MMC). In addition, we observed for the first time in a FA mouse model a marked in vitro growth defect of Fanca(-/-) progenitors, either when total BM or when purified Lin(-)Sca-1(+) cells were subjected to in vitro stimulation. Liquid cultures of Fanca(-/-) BM that were stimulated with stem cell factor plus interleukin-11 produced low numbers of granulocyte macrophage colony-forming units, contained a high proportion of apoptotic cells, and generated a decreased proportion of granulocyte versus macrophage cells, compared to normal BM cultures. Aiming to correct the phenotype of Fanca(-/-) progenitors, purified Lin(-)Sca-1(+) cells were transduced with retroviral vectors encoding the enhanced green fluorescent protein (EGFP) gene and human FANCA genes. Lin(-)Sca-1(+) cells from Fanca(-/-) mice were transduced with an efficiency similar to that of samples from wild-type mice. More significantly, transductions with FANCA vectors corrected both the MMC hypersensitivity as well as the impaired ex vivo expansion ability that characterized the BM progenitors of Fanca(-/-) mice.
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PMID:In vitro phenotypic correction of hematopoietic progenitors from Fanconi anemia group A knockout mice. 1220 Mar 63

The ligand for the Kit receptor tyrosine kinase is Kit ligand (Kitl; also known as mast cell growth factor, stem cell factor, and Steel factor), which is encoded at the Steel (Sl) locus of mice. Previous studies revealed that Kitl(Sl) mutations have semidominant effects; mild pigmentation defects and macrocytic, hypoplastic anemia occur in heterozygous mice, and more severe pigmentation defects and anemia occur in homozygotes. Lethality also occurs in mice homozygous for severe Kitl(Sl) mutations. We describe the effects of seven new N-ethyl-N-nitrosourea (ENU)-induced Kitl(Sl) mutations and two previously characterized severe Kitl(Sl) mutations on pigmentation, peripheral blood cells, and mouse survival. Mice heterozygous for each of the nine mutations had reduced coat pigmentation and macrocytosis of peripheral blood. In the case of some of these mutations, however, red blood cell (RBC) counts, hemoglobin concentrations, and hematocrits were normal in heterozygotes, even though homozygotes exhibited severely reduced RBC counts and lethality. In homozygous mice, the extent of anemia generally correlates with effects on viability for most Kitl(Sl) mutations; i.e., most mutations that cause lethality also cause a more severe anemia than that of mutations that allow viability. Interestingly, lethality and anemia were not directly correlated in the case of one Kitl(Sl) mutation.
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PMID:An allelic series of mutations in the Kit ligand gene of mice. II. Effects of ethylnitrosourea-induced Kitl point mutations on survival and peripheral blood cells of Kitl(Steel) mice. 1224 45

Transplantation of marrow stromal cells may provide a means of modulating hematopoiesis and serve as a form of cell therapy. We employed a murine transplant model using Sl/Sl(d) mice, which have macrocytic anemia due to defective expression of stem cell factor (SCF) on bone marrow stromal cells. Donor cells were derived from the complementary mutant strain W/W(v), which also exhibit anemia, due to mutations in c-kit, the SCF receptor expressed on hematopoietic stem cells. The strength of this model is that any correction of the Sl/Sl(d) anemia from the infusion of W/W(v) stromal cells can be attributed to the effect of the stromal cells and not to contaminating W/W(v) hematopoietic stem cells, a major concern in experiments involving wild-type animals. Cultured stromal cells were infused into unconditioned non-splenectomized Sl/Sl(d) mice. Engraftment of donor stromal cells reached levels of up to 1.0% of total marrow cells 4 months post transplant. However, stromal engraftment was not detectable in the spleen. Recipients of W/W(v) stroma showed a significant increase in the committed erythroid progenitors compared with those receiving Sl/Sl(d) stromal cells: 109 +/- 26 vs 68 +/- 5 CFU-E per 10(5) BMC, P = 0.002; 25 +/- 10 vs 15 +/- 5 BFU-E per 10(5) BMC, P = 0.037, for W/W(v) and Sl/Sl(d) stroma recipients, respectively. Despite this increase in erythroid progenitors, the anemia was not corrected. Our data suggest that in this murine model, splenic erythropoiesis may influence stromal cell therapy, and that higher levels of marrow engraftment may be necessary to obtain a clinically significant effect.
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PMID:W/Wv marrow stromal cells engraft and enhance early erythropoietic progenitors in unconditioned Sl/Sld murine recipients. 1247 78

Kit receptor tyrosine kinase and erythropoietin receptor (Epo-R) cooperate in regulating blood cell development. Mice that lack the expression of Kit or Epo-R die in utero of severe anemia. Stimulation of Kit by its ligand, stem cell factor activates several distinct early signaling pathways, including phospholipase C gamma, phosphatidylinositol 3-kinase, Src kinase, Grb2, and Grb7. The role of these pathways in Kit-induced growth, proliferation, or cooperation with Epo-R is not known. We demonstrate that inactivation of any one of these early signaling pathways in Kit significantly impairs growth and proliferation. However, inactivation of the Src pathway demonstrated the most profound defect. Combined stimulation with Epo also resulted in impaired cooperation between Src-defective Kit mutant and Epo-R and, to a lesser extent, with Kit mutants defective in the activation of phosphatidylinositol 3-kinase or Grb2. The impaired cooperation between the Src-defective Kit mutant and Epo-R was associated with reduced transphosphorylation of Epo-R and expression of c-Myc. Remarkably, restoration of only the Src pathway in a Kit receptor defective in the activation of all early signaling pathways demonstrated a 50% correction in proliferation in response to Kit stimulation and completely restored the cooperation with Epo-R. These data demonstrate an essential role for Src pathway in regulating growth, proliferation, and cooperation with Epo-R downstream from Kit.
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PMID:Functional and biochemical consequences of abrogating the activation of multiple diverse early signaling pathways in Kit. Role for Src kinase pathway in Kit-induced cooperation with erythropoietin receptor. 1248 28

Suppression of red blood cell production is a common complication of chemotherapy, causing anemia in a significant number of cancer patients. We have evaluated the sensitivity of human hematopoietic progenitors and erythroid precursor cells to chemotherapeutic drugs and found that probasophilic erythroblasts represent the stage of erythroid differentiation more vulnerable to the cytotoxic effects of myelosuppressive agents. Stem cell factor (SCF) supports proliferation and survival of early hematopoietic cells by binding to the c-kit receptor. In unilineage erythropoietic culture of CD34+ progenitors, short-term pretreatment of immature erythroid precursors with SCF results in protection from apoptosis induced by chemotherapeutic agents and restores normal proliferation and differentiation after removal of the cytotoxic stimulus. The levels of drug-induced caspase processing are significantly reduced in erythroblasts treated with SCF, indicating that activation of the c-kit receptor generates antiapoptotic signals acting before amplification of the caspase cascade. Accordingly, we found that SCF up-regulates Bcl-2 and Bcl-X L in erythroid precursors and that exogenous expression of these proteins protects erythroblasts from caspase activation and death induced by chemotherapeutic agents. These results suggest a possible mechanism for SCF-mediated protection of erythroid precursor cells from apoptosis and may contribute to devise new strategies for prevention and treatment of chemotherapy-induced anemia.
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PMID:Stem cell factor protects erythroid precursor cells from chemotherapeutic agents via up-regulation of BCL-2 family proteins. 1263 32

The molecular mechanism of anemia that is hyporesponsive to recombinant human erythropoietin (rHuEPO) in hemodialysis patients without underlying causative factors has not been investigated fully in hematopoietic stem cell system. Circulating CD34+ cells (1 x 10(4)) were isolated from rHuEPO hyporesponsive hemodialysis patients (EPO-H; n = 9), patients who were responsive to rHuEPO (EPO-R; n = 9), and healthy control subjects (n = 9). The patients with known causes of EPO hyporesponsiveness were eliminated from the current study. The cells were cultured in STEM PRO 34 liquid medium, supplemented with rHuEPO, IL-3, stem cell factor, and granulocyte-macrophage colony stimulating factor for 7 d and then transferred to a semisolid methylcellulose culture medium for performing burst forming unit-erythroid (BFU-E) colony assay. Expression of src homology domain 2 (SH2)-containing tyrosine phosphatase-1 (SHP-1), phosphorylated Janus kinase 2 (p-JAK2), and phosphorylated signal transducer and activator of transcription 5 (p-STAT5) was assessed with Western blot analysis. In EPO-H patients, SHP-1 antisense or scrambled S-oligos were included in the culture medium, and its effects were evaluated. The number of circulating CD34+ cells was not statistically different among the three groups, and their proliferation rates were similar for 7 d in culture. However, BFU-E colonies were significantly decreased in EPO-H patients compared with EPO-R and control groups. The mRNA and protein expression of SHP-1 and p-SHP-1 was significantly increased, whereas that of p-STAT5 was reduced in EPO-H patients. The inclusion of SHP-1 antisense S-oligo in culture suppressed SHP-1 protein expression associated with p-STAT5 upregulation, increase in p-STAT5-regulated genes, and partial recovery of BFU-E colonies. In EPO-H hemodialysis patients, the EPO signaling pathway is attenuated as a result of dephosphorylation of STAT5 via upregulation of SHP-1 phosphatase activity, and SHP-1 may be a novel target molecule to sensitize EPO action in these patients.
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PMID:The critical role of SRC homology domain 2-containing tyrosine phosphatase-1 in recombinant human erythropoietin hyporesponsive anemia in chronic hemodialysis patients. 1557 25

Erythropoiesis is regulated by a number of growth factors, among which stem cell factor (SCF) and erythropoietin (Epo) play a non-redundant function. Viable mice with mutations in the SCF gene (encoded by the Steel (Sl) locus), or its receptor gene c-Kit (encoded by the White spotting (W) locus) develop a hypoplastic macrocytic anemia. Mutants of W or Sl that are completely devoid of c-Kit or SCF expression die in utero of anemia between days 14 and 16 of gestation and contain reduced numbers of erythroid progenitors in the fetal liver. Likewise, Epo and Epo receptor (Epo-R)-deficient mice die in utero due to a marked reduction in the number of committed fetal liver derived erythroid progenitors. Thus, committed erythroid progenitors require both c-Kit and Epo-R signal transduction pathways for their survival, proliferation and differentiation. In vitro, Epo alone is capable of generating mature erythroid progenitors; however, a combined treatment of Epo and SCF results in synergistic proliferation and expansion of developing erythroid progenitors. This review summarizes recent advances made towards understanding the signaling mechanisms by which Epo-R and c-Kit regulate growth, survival, and differentiation of erythroid progenitors alone and cooperatively.
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PMID:Role of c-Kit and erythropoietin receptor in erythropoiesis. 1578 Sep 8


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