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 aim of this study was to evaluate the effect of stem cell factor (SCF) on the in vitro growth of bone marrow hematopoietic progenitors from patients with acquired severe aplastic anemia (AA) or Fanconi's anemia (FA). For this purpose, we studied 11 patients with acquired AA (5 at diagnosis, 6 after ALG treatment), 12 patients with FA, and nine normal controls. Bone marrow cells were plated in vitro for colony-forming unit granulocyte-macrophage (CFU-GM) (in the presence of granulocyte-macrophage colony-stimulating factor [GM-CSF]), and for burst-forming unit-erythroid (BFU-E) and CFU-granulocyte, erythroid, monocyte, megakaryocyte (CFU-GEMM) colonies (in the presence of erythropoietin and interleukin-3 [IL-3]), with or without 20 ng/mL of SCF. In normal controls, SCF enhanced the growth of CFU-GM colonies from 103 to 263 (median), of BFU-E from 168 to 352, and of GEMM colonies from 6 to 38/10(5) cells plated. In patients with acquired AA, SCF induced a significant enhancement of BFU-E growth (8 to 29; P = .01) and allowed the formation of GEMM colonies that were not scored in baseline culture conditions (0 to 8; P = .01). CFU-GM growth was enhanced (4 to 20), but not significantly (P = .3). This was true both for patients at diagnosis and after antilymphocyte globulin treatment. By contrast, 10 of 12 FA patients grew no CFU-GM, BFU-E, or CFU-GEMM colonies, with or without SCF. In two FA patients (one transfusion-dependent and one transfusion-independent), an enhancement of CFU-GM and/or BFU-E was observed. The lack of response of hematopoietic progenitor cells from FA patients to GM-CSF+SCF or IL-3+SCF was not dependent on a defective expression of cytokine receptor messenger RNAs. Northern blot analysis showed in marrow cells from acquired AA and FA patients the presence of normal transcripts for alpha- and beta-chains of GM-CSF/IL-3 receptor and for c-kit protein. In conclusion, SCF promotes the in vitro growth of hematopoietic progenitors in patients with acquired AA, but not in patients with FA, pointing out the intrinsic nature of the defect in the latter disorder.
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PMID:Effect of stem cell factor on colony growth from acquired and constitutional (Fanconi) aplastic anemia. 137 17

Many laboratory findings have demonstrated that the haemopoietic stem cell compartment is defective in aplastic anaemia (AA). AA bone marrow (BM) and peripheral blood (PB) are profoundly deficient in colony-forming cells, and AA progenitors fail to proliferate in long-term assays even in the presence of an intact stroma. Our study was designed to characterize some quantitative and qualitative aspects of the progenitor cell defect in AA. Using flow cytometric analysis of BM from new AA patients and from those recovering after immunosuppressive therapy, we determined that the numbers of CD34+ and CD33+ cells were markedly decreased in AA. Although PB neutrophil counts did not correlate with BM CD34+ cell numbers in acute disease, there was an association between the overall severity of the disease and the degree of CD34+ cell reduction. A decrease in BM CD33+ cells was a common finding in MDS patients, but reduction in CD34+ cells was found only in some hypoplastic MDS cases. Sorting experiments demonstrated lower plating efficiency for purified CD34+ cells from AA BM in comparison to controls. Thus, diminished colony formation of total BM appeared to result from both quantitative and qualitative defects. Based on the association between increased cycling and c-kit receptor expression on CD34+ cells, we found that the mitotically active CD34+ cells bearing the c-kit antigen were reduced in AA. With clinical improvement, CD34+ and CD33+ cells increased in correlation with PB parameters, but they did not return to normal values. Sorted CD34+ cells from recovered patents showed improved plating efficiency.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phenotypic and functional analysis of bone marrow progenitor cell compartment in bone marrow failure. 752 21

The proto-oncogene, c-kit, encodes a transmembrane tyrosine kinase receptor (KIT) and plays an important role in haemopoiesis. We have identified a 95 kD soluble form of KIT (S-KIT) in culture supernatant of human megakaryoblastic cell line, CMK. To study the physiological significance of S-KIT, we have established a sensitive sandwich ELISA system. Serum samples from healthy individuals contained detectable amounts of S-KIT. Next, we determined a total of 220 samples from 134 patients with haemopoietic disorders. A considerable number of patients with acute myeloid leukaemia (AML), especially those with more immature phenotypes (M0, M1 or M2) had elevated levels of serum S-KIT. Those levels decreased to the normal range after effective chemotherapy. In chronic myeloid leukaemia, patients with myeloid blastic crisis showed markedly elevated levels of serum S-KIT. In contrast, S-KIT levels decreased in cases with either acute or chronic lymphoid leukaemia. There was a tendency for patients with severe aplastic anaemia to show decreased levels, but it was not significant. In myelodysplastic syndrome, S-KIT levels appeared to vary by subsets, with higher concentration in more advanced forms of the disease. Although the functional role of S-KIT is not yet elucidated, these results suggest that the serum S-KIT levels may reflect the pathological states of various haematological disorders.
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PMID:Soluble c-kit molecule in serum from healthy individuals and patients with haemopoietic disorders. 757 39

A number of cytokines have been shown to have stimulatory activity on multipotent haematopoietic precursors. These include kit ligand (KL), interleukins (IL) 1, 3 and 6 and granulocyte macrophage-colony stimulating factor (GM-CSF). Using reverse transcriptase/polymerase chain reaction method (RT/PCR) we have examined the expression of these cytokines, the c-kit and IL-6 receptors, in long-term bone marrow culture (LTC) adherent layer cells in human bone marrow hypoplasia syndromes. Disorders studied include Fanconi's anaemia (FA, n = 16), idiopathic aplastic anaemia (AA, n = 11), Seckel's syndrome (n = 2), dyskeratosis congenita (n = 2), Shwachman-Diamond syndrome (n = 1), thrombocytopenia with absent radii syndrome (n = 1), acquired amegakaryocytosis (n = 1), paroxysmal nocturnal haemoglobinuria (n = 1) and acquired agranulocytosis (n = 1). IL-6 and GM-CSF expression appeared reduced in most patients with FA, suggesting that impaired production of these cytokines may contribute to the bone marrow failure seen in most patients with FA. In contrast, abundant IL-6 and GM-CSF expression were seen in most patients with AA when compared with the FA group and controls; these may be mediators of a stromal response in this disorder. No obvious differences were seen between the different patients' groups and controls in expression of the other cytokines or cytokine receptors studied.
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PMID:The expression of cytokine and cytokine receptor genes in long-term bone marrow culture in congenital and acquired bone marrow hypoplasias. 751 72

In this study we review our present understanding of the effect of stem cell factor (SCF) on the in vitro growth of hemopoietic progenitors from patients with acquired severe aplastic anemia (SAA). We have run three separate sets of experiments. First, we have tested the expression of receptor mRNAs for granulocyte-macrophage colony stimulating factor/interleukin 3 (GM-CSF/IL-3) and for c-kit protein on bone marrow (BM) cells from SAA patients. Molecular analysis revealed the presence of normal transcripts for alpha and beta chains of GM-CSF/IL-3 receptor and for c-kit protein by Northern blot analysis. Second, we have tested the in vitro response to SCF of BM cells derived from 11 SAA patients: SCF induced a significant enhancement of erythroid burst forming unit (BFU-E) growth (8 to 29, p = 0.01) and allowed the formation of granulocyte/erythroid/macrophage/megakaryocyte (GEMM) colonies which were not scored in baseline culture conditions (0 to 8, p = 0.01). Granulocyte-macrophage colony forming unit (CFU-GM) growth was also enhanced (4 to 20, p = 0.3). This was true for patients both at diagnosis and after antilymphocyte globulin (ALG) treatment. We concluded that SCF can promote the in vitro growth of hemopoietic progenitors in patients with acquired SAA. Third, we have tested the response to SCF of peripheral blood (PB) hemopoietic progenitors collected from patients receiving in vivo long-term treatment with granulocyte CSF (G-CSF). When PB cells were plated directly in the presence of GM-CSF there was no colony formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro effect of stem cell factor on colony growth from acquired severe aplastic anemia. 769 24

We investigated the effect of the human ligand for flt-3 (FL) on the committed progenitor colony formation of normal bone marrow (BM) (n = 9) and BM from four aplastic anaemia (AA) and three Diamond-Blackfan anaemia (DBA) patients. Methylcellulose committed progenitor cell assays were carried out using FL alone and in combinations with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3) and c-kit ligand (KL). FL alone had a limited, though significant, effect on the production of granulocyte-macrophage colony-forming unit (CFU-GM) colonies from normal BM and showed an additive effect with IL-3 and GM-CSF separately, but not in combination. FL did not increase the stimulation of KL and did not have an effect on the production of erythroid progenitor colonies. FL had no effect on the AA and DBA BMs studied.
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PMID:The effect of human flt-3 ligand on committed progenitor cell production from normal, aplastic anaemia and Diamond-Blackfan anaemia bone marrow. 855 52

To characterize the persistent abnormalities of hematopoiesis in aplastic anemia (AA) after immunosuppression with antilymphocyte globulin (ALG), we analyzed the quantity, phenotype, and growth properties of hematopoietic progenitor cells in 13 patients who received ALG treatment. Flow cytometry (FACS) revealed a deficiency of CD34+ cells in bone marrow (BM) of all patients. This deficiency was most severe (40-fold) in 4 patients in AA relapse. In 9 patients in remission, CD34+ cells were reduced 2-10-fold and showed no correlation with the ALG-induced improvement of peripheral blood cell counts. The proportion of CD34+ cells carrying c-kit receptors was abnormally low (2-10-fold below normal) in 5 of 13 AA patients. These patients also displayed low levels of c-kit mRNA by reverse transcription-polymerase chain reaction (RT-PCR). Furthermore, the CD34+ cell population was almost completely depleted of CD34+CD38- early hematopoietic progenitors in all AA patients. The proportion of CD34+ cells expressing lineage differentiation antigens CD33, CD71, and CD45RA in AA was increased, as compared to control BM. Formation of hematopoietic colonies by FACS-purified CD34+ cells was nearly absent in 4 relapsed patients, normal in 4 of 9, and decreased (up to 10-fold) in 5 of 9 patients in remission. The degree of impairment of colony-forming ability by AA progenitors correlated well with the reduction of CD34+ c-kit+ cells. The best proliferative response of CD34+ cells was observed in the presence of stem cell factor and, in some cases, fit3 ligand. Our results indicate that the disease process in AA depletes immature BM progenitors, thus providing a plausible explanation for persistent defects in colony-forming ability and long-term regenerative capacity of AA marrow after immunosuppression. Analysis of the immunophenotypes and the proliferative properties of purified progenitors may be useful for estimating degree of hematopoietic recovery in ALG-treated patients.
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PMID:Deficiency of CD34+ c-kit+ and CD34+38- hematopoietic precursors in aplastic anemia after immunosuppressive treatment. 870 44

Mice harboring the "white spotting" (W) locus have abnormalities in hematopoiesis due to one of various mutations of the c-kit proto-oncogene, which encodes the stem cell factor (SCF) receptor. The c-kit mutations identified in W mice cause diminished, absent or dominant negative receptor function. This study explores the hypothesis that acquired mutations of c-kit in the hematopoietic stem cell participate in the pathogenesis of aplastic anemia (AA). Genomic DNA was prepared from granulocytes and monocytes of 11 patients with acquired AA and one patient with a non-Fanconi's form of inherited AA. DNA was subjected to polymerase chain reaction (PCR) amplification and single-stranded conformation polymorphism (SSCP) analysis for all 21 exons of the c-kit gene. Two patients were heterozygous for a previously described polymorphism involving exon 17. Two other patient samples had an extra band on SSCP analysis of exon 10. DNA extracted from epithelial cells of one patient revealed the same SSCP pattern as that from the blood cells, suggesting that the alteration was in the germ-line. PCR-SSCP analysis of leukocyte DNA from 12 normal individuals revealed that 2 samples also had an extra band in exon 10. DNA sequencing of PCR-amplified and cloned DNA from the patients and the normal individuals with the aberrant SSCP results showed them all to be heterozygous for an ATG to CTG transition in codon 541, resulting in substitution of methionine by leucine in the transmembrane region of the protein. The same two patients and two controls were heterozygous for a silent change in codon 862 (exon 18). Matching serum samples from 4 of 6 AA patients tested had SCF levels more than two standard deviations above the normal mean value. These results suggest that neither c-kit mutations nor decreased soluble SCF levels are commonly involved in the pathogenesis of acquired AA.
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PMID:Analysis of c-kit gene integrity in aplastic anemia. 893 56

The role of known hematopoietic growth factors in the pathogenesis of aplastic anemia and congenital hypoplastic anemia has been extensively studied and no evidence has been obtained that deficiency of these factors contributes to the hypoproliferative state in these disorders. Clonal hematopoiesis seems to be present at least in a small percentage of cases of aplastic anemia, a finding that needs further investigation. Androgens were shown to be beneficial only for women with aplastic anemia treated with antilymphocyte globulin. Unrelated-donor bone marrow transplantation is becoming a realistic approach for children and very young adults with aplastic anemia, but in older groups the survival is very poor. New observations on abnormalities of lymphokines and cytokines in Fanconi's anemia have been described, but their pathogenetic significance remains unknown. A large number of studies have excluded the possibility that abnormalities of c-kit/SCF genes and their expression are responsible for the erythroid aplasia in Diamond-Blackfan syndrome. Cyclosporine was found to be an effective treatment for pure red cell aplasia associated with chronic lymphocytic leukemia. The cell membrane receptor for B19 parvovirus has been identified as the P antigen. Long-term studies showed that in 20% of patients with homozygous sickle cell disease, infection by B19 does not cause erythroid aplasia.
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PMID:Aplastic anemia and pure red cell aplasia. 937 Dec 75

Defective marrow stroma or microenvironment have been proposed as one of several mechanisms to account for bone marrow failure in aplastic anaemia (AA). Stem cell factor (SCF), the ligand for the c-kit receptor, is produced mainly by marrow stromal cells and seems to reflect the haemopoietic function of bone marrow stroma. We measured the plasma levels of soluble SCF in 8 7 patients with AA and investigated the production of soluble SCF by the marrow stromal cells of 46 patients with acquired AA. The mean plasma SCF concentrations in the AA patients and normal controls were not significantly different (1098 +/- 398 pg/ml versus 1160 +/- 316 pg/ml, respectively), and there was no significant correlation between the peripheral blood counts and the SCF concentrations. However, the mean SCF concentration in patients who received prednisolone +/- anabolic steroids at the time of sampling was significantly lower than that in the patients who did not receive both agents. We did not find any correlation between the changes in SCF concentrations and the response to immunosuppressive therapy, although it did increase significantly after bone marrow transplantation. The ability of marrow stromal cells to release soluble SCF did not differ significantly between the patients with AA and normal controls. We conclude that soluble SCF production does not appear to be altered in patients with AA and that defective production of soluble SCF is unlikely to be the cause of AA in most patients.
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PMID:Plasma levels and production of soluble stem cell factor by marrow stromal cells in patients with aplastic anaemia. 937 70


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