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)

To assess p53 expression in the hematopoietic cells of the bone marrow in premalignant as well as malignant conditions, we examined immunohistochemically bone marrow biopsies from patients with myelodysplastic syndromes (MDS, n = 51), acute myeloid leukemia (n = 42) and as a nonneoplastic condition, aplastic anemia (n = 20) and samples from individuals who had no hematological disorder (control, n = 12). Nuclear accumulation of p53 protein was found in seven of 51 patients with MDS (14%) and two of 42 acute myeloid leukemia patients (5%), whereas patients with aplastic anemia and control subjects were uniformly negative for p53 protein. In the bone marrow of patient with MDS, p53-positive cells constituted about 5 to 30% of the total bone marrow cells. Two-color immunohistochemical analysis revealed that the p53-positive cells were also positive for the myeloid cell marker. Half of the MDS cases that evolved to overt leukemia (seven of 14) exhibited positive p53 reaction in the bone marrow at the time of initial diagnosis. This frequency (50%) was significantly higher than that in de novo acute myeloid leukemia cases. All of the seven MDS cases that exhibited p53 expression at the time of initial diagnosis developed overt leukemia later, and p53 expression was maintained throughout the progression of MDS. The results suggest that p53 mutations that occur in the myeloid cells in MDS may confer a growth advantage to these cells resulting in the progression to overt leukemia. Thus, immunohistochemical examination for p53 is very useful for predicting the evolution to overt leukemia from MDS.
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PMID:p53 expression in myeloid cells of myelodysplastic syndromes. Association with evolution of overt leukemia. 805 92

Patients with Fanconi anemia (FA) have an extraordinary predisposition to acute myelogenous leukemia (AML). The genetic mechanisms underlying the neoplastic transformation of FA hematopoietic cells are unknown. In this study, we have investigated the molecular features of hematopoiesis in the course of FA at different stages of the disease, including aplastic anemia, myelodysplastic syndrome (MDS), and AML. The analysis focused on defining the clonality status of FA hematopoiesis as well as the putative involvement of N-ras, a dominantly acting oncogene, and p53, a tumor suppressor gene, which are known to play a role in human hematopoietic tumors. Clonality of hematopoiesis was assessed by testing X-chromosome inactivation at the DXS255 locus, which displays different methylation patterns according to the activation status of the corresponding X homolog. Five out of seven FA cases analysed for clonality displayed monoclonal hematopoiesis, including one case at the aplastic anemia stage, three cases with MDS and one with AML. Mutations of the N-ras and p53 genes were studied by a combination of single strand conformation polymorphism (SSCP) analysis and direct sequencing of the PCR product in the bone marrow and/or peripheral blood of 18 FA patients (seven with aplastic anemia, seven with MDS, four with AML). Only normal N-ras and p53 sequences were detected in all cases analyzed. These results suggest that monoclonal hematopoiesis is a frequent finding in the course of FA and may precede the onset of neoplasia in some cases. The genetic mechanisms underlying FA-associated leukemogenesis appear to be independent of N-ras and p53 mutations, which are relatively frequent events in myeloid tumors associated with other hematologic disorders.
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PMID:Clonality studies and N-ras and p53 mutation analysis of hematopoietic cells in Fanconi anemia. 805 73

In order to investigate the involvement of apoptosis in the pathogenesis of aplastic anaemia (AA) we measured the expression of the Fas receptor (membrane protein that triggers apoptosis), Fas ligand (FasL), bcl-2 (cytoplasmatic protein that blocks apoptosis) and p53 (nuclear protein that induces apoptosis) in CD3 and CD19 lymphocytes from the peripheral blood or bone marrow of controls, patients with AA, aplastic anaemia in complete remission (AA-CR) and multiply transfused patients without aplastic anaemia. The Fas receptor was overexpressed in both T and B lymphocytes from the peripheral blood and bone marrow from patients with AA. These abnormalities were not detected in AA-CR or multiply transfused patients. CD3/FasL cells were not increased and no FasL expression was detected in B lymphocytes. Bcl-2 was highly expressed in lymphocytes from controls, AA, AA-CR and multiply transfused patients (> 99% of positive cells) whereas p53 was not detected in any group. To further characterize the functional activity of the Fas receptor we performed a Fas-induced apoptosis assay in peripheral blood lymphocytes using an anti-Fas monoclonal antibody. The crosslinking of the Fas receptor transduced an increased apoptotic signal in lymphocytes from AA patients, but not in lymphocytes from controls, AA-CR patients or multiply transfused patients. Taken together, these data suggest that a Fas-based mediated apoptosis without the apparent participation of bcl-2 or p53 is a possible mechanism of lymphocyte depletion in patients with AA. In addition, these findings suggest that Fas expression is a continuous event occurring from progenitor bone marrow cells to mature cells.
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PMID:Fas-mediated apoptosis with normal expression of bcl-2 and p53 in lymphocytes from aplastic anaemia. 958 Feb 7

Among patients with bone marrow failure, differentiating acquired aplastic anemia (AA) from hypocellular refractory anemia (hypo RA) can be a difficult and challenging task. Morphological, cytochemical, immunocytochemical, and cytogenetic studies may provide tools for discriminating between both entities. In addition, differences in the pattern of proliferation and apoptosis of bone marrow cells in AA and in the myelodysplastic syndrome have been reported. Because of the correlation between p53 and apoptosis, we examined the overexpression of p53 on bone marrow biopsies in RA and AA. Our study included 14 patients with hypo RA, 14 patients with hypercellular (hyper) RA, ten patients with classic acquired AA, and 37 hematologically normal individuals. p53 was overexpressed in eight (57%) hypo RA patients and 11 (79%) hyper RA patients. All normal individuals and patients with AA showed no overexpression of p53 in their marrow. These results were statistically significant:p < 0.01 (AA vs hypo RA), p<0.001 (AA vs hyper RA), while the difference between hypo RA and hyper RA was not statistically significant. We conclude that p53 overexpression in bone marrow biopsies is a valuable tool for studying bone marrow failure and may provide additional information to help differentiate hypo RA from acquired AA.
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PMID:Significance of p53 overexpression in bone marrow biopsies from patients with bone marrow failure: aplastic anemia, hypocellular refractory anemia, and hypercellular refractory anemia. 987 62

There is a growing interest in studying cell cycle and apoptosis in the myelodysplastic syndromes (MDS). p53 has been a major target of several studies. We examined the impact of antibody selection on p53 overexpression in bone marrow (BM) biopsies of 28 patients with refractory anemia (RA) in addition to 10 cases of aplastic anemia (AA) using three antibodies DO-7, PAb 1801, and PAb 240. DO-7 was positive in 68%, PAb 1801 in 18% and PAb240 in 4% of RA patients. All three antibodies were negative in AA. We conclude that antibody selection is an important variable in studying p53 in MDS regardless of the method of fixation or decalcification of BM trephine biopsies.
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PMID:P53 overexpression in bone marrow biopsies in refractory anemia and aplastic anemia: impact of antibody selection. 1108 82

Making a morphologic distinction between hypocellular refractory anemia (hypo RA) and aplastic anemia (AA) is difficult. To investigate the significance of hemoglobin F-containing erythroblasts (F-blasts) and p53 expression in making the distinction between hypo RA and acquired AA, we immunohistochemically assessed F-blasts and p53 in bone marrow specimens from 16 patients with hypo RA, 31 patients with acquired AA, and 15 hematologically normal individuals. F-blast production was elevated in 87.5% (14/16) of patients with hypo RA, but in only 3.2% (1/31) of patients with AA (P < .01). p53 was overexpressed in 75.0% (12/16) of hypo RA patients and in 6.4% (2/31) of AA patients (P < .01). The mean contents of F-blasts and p53-positive cells in patients with hypo RA were 6.31% +/- 3.27% and 7.54% +/- 4.36%, respectively, of all bone marrow cells, which were significantly higher than for patients with AA (0.35% +/- 0.46% and 0.58% +/- 1.29%, P < .01). In conclusion, a high prevalence of elevated F-blast production is noted in hypo RA, suggesting that the assessment of F-blasts in bone marrow can be used as an additional tool for differentiating hypo RA from acquired AA.
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PMID:F-blast is a useful marker for differentiating hypocellular refractory anemia from aplastic anemia. 1199 52

There are several common themes that are emerging from our expanding knowledge about the inherited bone marrow failure syndromes. Patients have a spectrum of birth defects, which are relatively characteristic for each syndrome. but overlap in features such as poor growth. radial ray anomalies, and involvement of skin, eyes, renal, cardiac, skeletal, and other organs. Within each syndrome the composition and severity of the physical phenotype varies widely, and it may require the astute observer to make the correct diagnoses in the milder cases. There is also a wide spectrum to the hematologic picture. These range from single cytopenias such as DBA, SCN, and TAR, which do not develop pancytopenia, to SD and Amega patients who begin with deficiency of a specific single lineage, but evolve to aplastic anemia, to patients with FA or DC, who may present with a deficiency of any one of the cell lines, but almost inevitably end up with full-blown aplastic anemia. Acute myeloid leukemia has been observed in FA, DBA, DC, SD, SCN, and Amega, although not yet in TAR patients. MDS has also been reported in all of the same disorders as AML, although whether it is a preleukemic condition or an independent bone marrow dyspoiesis is not yet clear. Solid tumors are also now appearing in patients whose underlying disease involves hematopoiesis and physical development. These tumors occur at much younger ages than in the general population, in patients who do not appear to have the usual risk factors, and have patterns that are characteristic to the syndrome, such as head and neck and gynecologic cancers in FA and DC, and osteogenic sarcomas in DBA. The other syndromes have not yet been reported to have a propensity for solid tumors. Several genes have been identified that are mutant in some of the syndromes, although the pathophysiology is still not entirely clear. The inheritance patterns include X-linked recessive, autosomal dominant, autosomal recessive, and even mitochondrial. The FA gene products appear to cooperate, and are important in the pathways involved in response to DNA damage. However, the role of this pathway in developmental defects, hematopoietic failure, and the specific malignancies in FA is not fully elucidated. The DC gene products are important for maintenance of telomere length, which may have relevance to development of aplastic anemia and malignancies, but the relation to the physical phenotype is less apparent. The role of mutations in c-mpl in Amega is more straightforward. since the gene codes for the receptor for thrombopoietin. which is the hormone required for megakaryocyte and platelet development; patients with mutant c-mpl do not have birth defects. The role of mutations in RPS19 in erythropoiesis or developmental defects in DBA patients is not obvious, and the increased frequency of osteogenic sarcomas suggests that at least that subset of patients may have a mutant tumor suppressor gene (such as p53, the mutant gene in Li-Fraumeni syndrome) [68]. Although patients with SCN have mutations in neutrophil elastase, patients with similar mutations may have relatively benign cyclic neutropenia, or may even have normal neutrophil levels [69,70]. The mitochondrial gene deletions in Pearson's Syndrome result in variable degrees of acidosis, and varied organ involvement due to heteroplasmy. Thus, the disorders included under the rubric "inherited bone marrow failure syndromes" have clinical. hematologic, oncologic, and genetic diversity.
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PMID:Bone marrow failure syndromes in children. 1243 Jun 21

Two cases of acute myeloblastic leukemia (AML) evolving from aplastic anemia are presented. The first case was diagnosed 18 years ago, and treatment with bolus methylprednisolone, prednisolone, and androgens resulted in partial hematological response. Severe pancytopenia recurred, and AML M0 by French-American-British classification developed. The second case was diagnosed 7 years ago. The patient had HLA DRB1*1501, and treatment with granulocyte colony-stimulating factor (G-CSF), cyclosporine, and methenolone resulted in complete hematological response. Thrombocytopenia recurred and did not respond to cyclosporine and methenolone or to later treatment with antithymocyte globulin, and AML M1 developed. Cytogenetic studies demonstrated 7q- in the first patient and +8 in the second patient. No mutations of N-ras or p53 were observed in either patient. These patients were treated with cytosine arabinoside, aclacinomycin, and G-CSF (CAG) chemotherapy, and the number of leukemic cells decreased substantially. However, pancytopenia after CAG chemotherapy persisted, and the first patient died of pneumonia and the second patient of cerebral hemorrhage.
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PMID:Two cases of acute myeloblastic leukemia evolving from aplastic anemia. 1284 85

P53 mutation has been reported in various solid tumors, acute leukemia and myelodysplastic syndrome (MDS), but the diagnostic significance of p53 in MDS remains to be determined. The purpose of the present paper was to examine p53 mutation and immunostaining of the same patients, because there have been few reports of simultaneous analysis of these markers. Seven p53 mutations were observed among 37 MDS and 11 cases of overt leukemia transformed from MDS (MDS-OL). Mutated p53 mainly observed in high-risk MDS had more intense p53 staining than in MDS with wild-type p53 overexpression. Aplastic anemia (AA) produced no p53 staining. The percentage of p53 staining in MDS (71%) was higher than that of mutated p53 (11%) but did not reach 100% of MDS cases studied, therefore the authors attempted to differentiate MDS, especially refractory anemia (RA) and AA, using a combination of p53 immunostaining, hemoglobin F (HbF) immunostaining and chromosome abnormality, because HbF of erythroblasts was reportedly observed in MDS RA but not in AA. Most MDS/MDS-OL (47/48) had at least one positive marker. Among 11 AA cases, only two were positive for HbF. The present results suggest that the combination of these three markers is useful to discriminate MDS from AA.
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PMID:Characterization of myelodysplastic syndrome and aplastic anemia by immunostaining of p53 and hemoglobin F and karyotype analysis: differential diagnosis between refractory anemia and aplastic anemia. 1847 14

Chloramphenicol is a broad-spectrum antibiotic used for the treatment of many infectious diseases and has become one of the major seafood contaminants. Hematologic disorders such as aplastic anemia and leukemia induced by chloramphenicol are a major concern. However, the mechanism underlying chloramphenicol-induced leukemogenesis is not known. By investigating the effects of chloramphenicol on the activation of mouse T cells stimulated with anti-CD3 antibody or staphylococcal enterotoxin B, we found that chloramphenicol induces the differentiation of activated T cells into lymphoblastic leukemia-like cells, characterized by large cell size, multiploid nuclei, and expression of CD7, a maker for immature T cells and T-cell lymphocytic leukemia, thus phenotypically indicating differentiation toward leukemogenesis. High expression of cyclin B1, but not p53, c-myc, and CDC25A, was detected in chloramphenicol-treated activated T cells, which may relate to abnormal cell differentiation. Chloramphenicol inhibited the activation-induced cell death of mouse and human T-cell receptor-activated T cells by down-regulating the expression of Fas ligand. Our findings show that abnormal cell differentiation and inhibition of apoptosis may contribute to the development of leukemia associated with clinical applications of chloramphenicol.
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PMID:Chloramphenicol induces abnormal differentiation and inhibits apoptosis in activated T cells. 1855 35


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