UMLS:C0026986 - FACTA Search

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Query: UMLS:C0026986 (myelodysplastic syndrome)
14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Frequent apoptosis in the bone marrow of patients with myelodysplastic syndromes (MDS) was demonstrated on frozen sections using the terminal deoxytransferase (TdT)-mediated dUTP nick end labeling (TUNEL) method. The overall mean percentage of TUNEL-positive cells was about 17% in the bone marrow of MDS, while bone marrow from control cases exhibited a mean of 3.4% (P < 0.001). To elucidate the mechanism of apoptosis in bone marrow cells of MDS, the expression of Fas antigen and Fas ligand (FasL) was examined by RT-PCR and immunohistochemistry. All MDS cases showed expression of Fas mRNA (12/12) and most exhibited an expression of FasL mRNA (10/12) by RT-PCR. Basically, control cases did not show positive signals for Fas and FasL mRNA, however, a very weak band was detected in three cases (3/10) for Fas and in one case (1/10) for FasL mRNA by RT-PCR. Immunohistochemical examination revealed positive staining for Fas (11/12) and FasL (12/12) in the bone marrow of MDS, while all the bone marrow samples from control cases were negative for anti-Fas (0/15) and for anti-FasL (0/15) antibody. Double staining clarified that TUNEL-positive apoptotic cells expressed Fas antigen on the cell surface, although not all Fas-positive cells were TUNEL positive. The Fas-positive cells of MDS bone marrow included hematopoietic cells expressing CD34 antigen, neutrophil elastase, a marker for myeloid series of cells, or glycophorin A, a marker for erythroid cells. However, CD68-positive cells which were macrophage lineage cells, did not express Fas antigen strongly. In contrast, positive staining for FasL was detected in hematopoietic cells and CD68-positive cells in the bone marrow of MDS. These results suggest that the Fas-FasL system plays an important role in inducing apoptosis in the bone marrow of MDS and works in an autocrine (hematopoietic cell-hematopoietic cell interaction) and/or paracrine (hematopoietic cell-stromal cell interaction) manner.
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PMID:Localization of Fas and Fas ligand in bone marrow cells demonstrating myelodysplasia. 955 5

Myelodysplastic syndrome (MDS) is a group of hematopoietic disorders characterized by peripheral cytopenias in the presence of normo- or hypercellular dysplastic marrow. It has been suggested that premature intramedullary apoptosis may contribute to this phenomenon. We used terminal dUTP nick-end labeling (TUNEL) of bone marrow biopsy specimens and cytocentrifuge preparations from patients with MDS and a variety of other hematopoietic disorders to determine whether there is increased intramedullary apoptosis in MDS and whether any such effect is specific to MDS. TUNEL labeling of bone marrow from 24 patients with MDS revealed significant positivity in 10 of 11 patients with refractory anemia (RA), five of seven with RA and excess of blasts (RAEB), all three patients with RAEB in transformation (RAEB-t), and all three patients with RA with ring sideroblasts (RARS). The percent of positive cells ranged from 5 to 50% but showed no apparent correlation with morphological subtype. In a series of 29 patients with acute leukemia, 17 showed significant positivity (13 of 13 with myeloid disease: three M1, seven M2, one M3, two M4; four of 16 patients with lymphoid disease: one Burkitt-type lymphoma, two null acute leukemia, and one common acute lymphoid leukemia). Intramedullary apoptosis was associated with myeloid or early committed progenitor cells and was highest in secondary acute myeloid leukemia (AML). Normal bone marrow samples from 12 individuals showed no evidence of apoptosis. Our results suggest that an increased level of intramedullary apoptosis is apparent in both patients with MDS and those with AML; those with secondary AML have the highest levels. The relative absence of such findings in lymphoid malignancy suggests that the apoptotic pathways are different in this lineage.
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PMID:Spontaneous intramedullary apoptosis is present in disorders other than myelodysplasia. 976 38

The paradox of peripheral cytopenias despite cellular bone marrow (BM) observed in myelodysplastic syndromes (MDS) has been associated with excessive intramedullary apoptosis of hematopoietic cells. Since MDS is regarded as a stem cell disorder, the present studies were undertaken to examine the relative susceptibility and propensity of early progenitor CD34+ cells to undergo apoptosis as compared to more maturing/matured CD34- cells. Five serial studies were performed on 4 independent groups of 36 newly diagnosed MDS patients. First, in 2 separate groups of 16 and 8 patients each, measurement of the extent of apoptosis in CD34+ and CD34- fractions of the BM aspirate mononuclear cells was carried out using independent biparametric flow cytometry methods, CD34 labeling/terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) (n = 16), and CD34 labeling/reduced uptake of nucleic acid staining dye LDS751 (n = 8). The difference in the median degrees of apoptosis in CD34+ vs. CD34- cells was not statistically significant by either technique (P = 0.583 and P = 0.674 for TUNEL and LDS751, respectively). In the next group of 4 MDS patients, a double-labeling was performed on plastic embedded marrow biopsy sections, to detect CD34 antigen with specific monoclonal antibody and apoptosis by in situ end labeling (ISEL) of fragmented DNA. Despite high overall apoptosis (56.2% +/- 18.4%), only an occasional CD34+ cell was found to be simultaneously labeled with ISEL. Finally, in the last group of 8 MDS patients, CD34+ cells were separated from CD34- cells on affinity column and cultured in serum containing medium for 4 hours. At 0- and 4-hour time points, ISEL was carried out to label apoptotic cells. In addition, a fluorometric assay was employed to estimate the activity of a proapoptotic enzyme, Caspase 3. Both the net increase in % ISEL labeled cells (apoptotic index or AI) and Caspase-3 activity were significantly lower in CD34+ cells as compared to CD34- cells (AI, 0.87% +/- 0.5% vs. 3.97% +/- 1.4%, n = 6, P = 0.028 and Caspase-3 Units/mg protein, 46.9 +/- 25.0 vs. 71.7 +/- 23.03, n = 5, P = 0.042, respectively). We conclude that when estimated in a total population of mononuclear cells, CD34+ cells and CD34- cells show comparable degrees of apoptosis. However, once separated the CD34+ fraction demonstrates lower propensity to undergo apoptosis, thereby suggesting the CD34- fraction as being a possible source for proapoptotic signaling.
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PMID:The relative extent and propensity of CD34+ vs. CD34- cells to undergo apoptosis in myelodysplastic marrows. 1022 52

Background: Mutations in members of the ras gene family (H-ras, K-ras, and N-ras) have been identified in various human malignancies. A variety of techniques have been used to test for ras mutations. Methods and Results: A simplified reverse dot blot (RDB) assay was used in this study. Polymerase chain reaction products were hybridized to nitrocellulose membrane-fixed synthetic probes (20 nucleotides long) specific for codons 12, 13, and 61 of H-, K-, and N-ras mutations and their wild-type sequences. No special treatment or modification of the probes was necessary to obtain adequate results in overnight film exposure when the polymerase chain reaction was carried out using (32)P-end labeled primers. It was demonstrated that this simplified RDB assay can also be used with fluorescein-11-dUTP and a chemiluminescence detection system. The RDB assay is more reliable than the single-strand conformation polymorphism (SSCP) assay. By comparison, the SSCP assay is significantly less sensitive and less specific. It was confirmed with sequencing that 11 (12%) of 93 SSCP assays were false positive and 2 (2%) were false negative, whereas no false positive or false negative RDB assay was detected. The RDB assay also provides more additional detailed information about the specific point mutation and amino acid change, which may have clinical implications in some tumors. Conclusions: The RDB assay is very sensitive and able to detect mutations when the mutant allele is in 1% of the cells and can be used to detect minimal residual disease, particularly in some cases of leukemia and myelodysplasia.
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PMID:Simplified Reverse Dot Blot Analyses for Detecting of ras Oncogene Mutations. 1046 6

In patients with myeloid malignancies, cell-mediated immunity is often suppressed, being most profound in those with advanced disease. Such immune dysfunction, as demonstrated in many patients with chronic lymphocytic leukaemia (CLL) and myelodysplastic syndrome (MDS), may, at least in part, be due to altered expression of the CD3-zeta chain, which is an important component of the T-cell receptor (TCR). We speculated that impaired expression of the TCR-zeta chain would be evident in peripheral blood T cells of patients with chronic myeloid leukaemia (CML) and that such an abnormality would result in an increased ex vivo susceptibility to apoptosis. In this study, we demonstrated that, compared with normal controls, zeta chain expression was significantly downregulated in all of the T-cell subsets (P < 0.009) in more than 90% of CML patients. In addition, there was a significantly lower expression of the CD3-epsilon chain (P < 0.001) in patients than in controls. In those patients with abnormal zeta chain expression, the proportion of lymphocytes with spontaneous DNA fragmentation, as determined by terminal deoxynucleotide transferase-mediated dUTP-biotin nick-end labelling (TUNEL) assays, was also significantly higher (P < 0.002) than controls. From all of the patients tested, it was possible to upregulate partially zeta chain expression and hence to reduce the susceptibility to apoptosis by cross-linking the T cells with interleukin (IL)-2, interferon (IFN)-alpha or immobilized CD3. In addition, such cross-linked T cells showed a significantly higher capacity to proliferate than the native CML T cells.
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PMID:Impaired expression of the CD3-zeta chain in peripheral blood T cells of patients with chronic myeloid leukaemia results in an increased susceptibility to apoptosis. 1112 43

An increased bone marrow (BM) apoptosis is one of the mechanisms responsible for the ineffective hematopoiesis of myelodysplastic syndromes (MDS). It is controversial whether the excessive apoptosis in myelodysplasia predominantly involves the subset of progenitor cells or of maturing cells. We investigated the degree of apoptosis in MDS BM and its differences from normal marrow in relation to CD34 antigen expression. A double-labelling technique that combined the Tdt-mediated dUTP nick end labelling (TUNEL) method with immunocytochemistry for CD34 antigen was used on BM slides of 18 MDS patients and 11 controls. The apoptotic rate (AR) appeared significantly higher in CD34-negative than in CD34-positive cell subsets both in myelodysplastic and in normal BM. When MDS and normal CD34-negative cell populations were compared, a greater AR in MDS CD34-negative cells was found, while no statistical difference in AR resulted from the comparison between MDS and normal CD34-positive cell populations. Our results suggest that in myelodysplastic as well as in normal BM the apoptotic phenomenon predominantly involves the maturing cells. The increase in apoptotic levels which can be observed in myelodysplastic compared to normal BM seems to be mainly due to an increase in apoptosis in the differentiated cell population.
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PMID:Apoptosis in relation to CD34 antigen expression in normal and myelodysplastic bone marrow. 1248 20

In myelodysplasia (MDS) the precise mechanism of ineffective erythropoiesis is not fully elucidated, but it is suggested that apoptosis may contribute to this process. We performed TdT-mediated dUTP-nick end labelling (TUNEL) staining of paraffin embedded bone marrow specimens to assess the amount of apoptotic cells in 21 MDS patients (7 RA, 3 RARS, 5 RAEB, 3 RAEB-T, 3 CMML) and five normal controls. In 10 MDS patients the TUNEL assay was performed in combination with immunostaining for Glycophorin-A (GpA) to determine apoptosis in the maturing erythroid compartment. To assess the proliferation of the bone marrow cells the expression of Ki-67 antigen was used as a marker. The mean apoptotic index (AI) in MDS patients was not increased (2.3 +/- 3.0% in MDS versus 4.8 +/- 1.2% in normal controls (P < 0.05)). Moreover, no significant difference in mean AI was observed in the GpA+ compartment between MDS and normal controls (0.8 +/- 0.2% versus 0.6 +/- 0.1%). In addition the different FAB-classifications and the different International Prognostic Scoring System (IPSS)-risk groups showed no significant differences between the subgroups. The expression of Ki-67, as marker for proliferative activity, in the GpA+ compartment from MDS did not differ significantly from normal controls (84.0 +/- 12.2% versus 79.9 +/- 20.2%). Our findings suggest that the observed increased apoptosis in in vitro culture assays is related to the detachment of the cells from the microenvironment leading to an increased susceptibility to apoptosis.
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PMID:Limited numbers of apoptotic cells in fresh paraffin embedded bone marrow samples of patients with myelodysplastic syndrome. 1523 68

To explore the correlation between the cellular inhibitors of apoptosis proteins (cIAPs) and the apoptosis of myelodysplastic syndrome (MDS) cell line (RAEB type) cells induced by aclacinomycin (ACM), the apoptosis of MDS cell line MUTZ-1 cells induced by ACM was analyzed with terminal deoxyribonucleotidy transferase mediated dUTP-biotin nick end labeling (TUNEL) technique. By using semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR), the expression levels of cIAP-1 and cIAP-2 mRNA in MUTZ-1 cells were assayed. The results showed as follow: (1) Using 0.5 micromol/L, 1.0 micromol/L ACM treated cells for 24 hours, the relative expression level of cIAP-1 mRNA (cIAP-1/GAPDH) was lower than those in the untreated cell group (P=0.002, 0.0002, respectively). (2) Using 0.5 micromol/L ACM treated for 6, 12, 24 hours, the relative expression level of cIAP-1 mRNA was 0.95 +/- 0.04, 0.73 +/- 0.05, 0.38 +/- 0.07, respectively and the relative expression level of cIAP-1 mRNA was correlated negatively with the time treated by ACM (r=-0.996, P <0.01). (3) Using 0.5 micromol/L ACM treated for 3, 6, 12, 24 hours, the relative expression level of cIAP-2 mRNA was 1.17 +/- 0.06, 0.91 +/- 0.03, 0.69 +/- 0.07 and 0.00 +/- 0.00, respectively and relative expression level of CIAP-2 mRNA was correlated negatively with the time treated by ACM (r=-0.091, P <0.01). (4) The percentages of TUNEL positive cells were correlated negatively with the relative expression level of CIAP1 and CIAP2 mRNA (r=-0.984, -0.959 and P=0.002, 0.013 respectively) when treated with increasing concentration of ACM. In conclusion, ACM can induce significantly MUTZ-1 cell apoptosis via suppressing expression of anti-apoptotic gene cIAP-1 and cIAP-2 mRNA.
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PMID:[Study on the relationship between the inhibitors of apoptosis proteins and the apoptosis of myelodysplastic syndrome cell line cells induced by aclacinomycin in vitro]. 1549 19

To explore the expression of insulin-like growth factor receptor type I (IGF-IR) and its relationship to apoptosis in hematopoietic cells of MDS and AML marrow, bone marrow nucleated cells from 16 patients with myelodysplastic syndrome (MDS) and 16 patients with acute myeloid leukemia (AML) were collected for analysis, respectively. Another 16 normal donors' marrow samples were taken as controls. Immunocytochemical method (APAAP) and TdT-mediated dUTP nick end labeling (TUNEL) fluorescence were used simultaneously on cytospins of nucleated cells from these patients. Then, the ratios of IGF-IR positive cells and apoptosis cells in all nucleated cells were counted separately. The results showed that (1) there was a higher IGF-IR expression rate (56.8 +/- 14.3)% in nucleated cells of MDS marrow than that in normal marrow (40.4 +/- 9.6)% (P < 0.01). Also IGF-IR positive rate in AML marrow (86.8 +/- 13.8)% was significantly higher than that in normal marrow (P < 0.01). Furthermore, IGF-IR had higher expression in AML marrow when compared to MDS marrow (P < 0.01); (2) apoptosis in nucleated cells of MDS marrow (5.4 +/- 3.0)% was significantly higher than that in normal marrow (1.2 +/- 0.9)% (P < 0.01) and AML marrow (0.3 +/- 0.4)% (P < 0.01), while there was less apoptosis in AML marrow than that in normal marrow (P < 0.01); (3) apoptosis occurred mainly in IGF-IR negative cells (9.0 +/- 4.8)% and less in IGF-IR positive cells (1.4 +/- 2.4)% (P < 0.01). IGF-IR expression showed negative correlation with apoptosis (r = -0.852, P < 0.01); (4) IGF-IR of MDS nucleated cells in RAEB/RAEB-t/CMML expressed higher than that in RA/RAS (64.1 +/- 3.2% vs 53.5 +/- 16.2%) subgroup, although no significant difference was found (P > 0.05); and apoptosis in RAEB/RAEB-t/CMML subgroup was lower than that in RA/RAS cases (3.1 +/- 2.1% vs 6.4 +/- 2.8%) (P < 0.05); (5) IGF-IR positive rate in nucleated cells of MDS and AML marrow showed positive correlation with blast rate (r = 0.677; P < 0.01). It is concluded that there is overexpression of IGF-IR in marrow nucleated cells in MDS and AML cases. And it seems that the overexpression of IGF-IR may suggest some malignant proliferation tendency and suppress cell apoptosis through some mechanism in these malignant hematologic ailments. So, anti-IGF-IR will become a new approach for therapy of MDS and AML.
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PMID:[Expression of insulin-like growth factor receptor type I in marrow nucleated cells from hematologic malignancies and its anti-apoptotic effect]. 1597 47

To verify the expression of type 1 insulin-like growth factor receptor (IGF-IR) and its impact on hematopoietic cells apoptosis in myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML), marrow samples from 16 patients with MDS and 16 patients with AML were examined along with 16 healthy donors as controls. Immunocytochemical methods (alkaline phosphatase anti-alkaline phosphatase) and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (fluorescence) were used simultaneously on nucleated cell cytospins. The ratio of IGF-IR positive cells and apoptotic cells as well as the relationship between them were then analyzed separately. A quantitative real-time reverse transcriptase-polymerase chain reaction (PCR) was administrated for six MDS cases and two normal controls to validate IGF-IR expression detected by immunochemistry. In our assay, IGF-IR appeared to have higher to lower expression rate in turn from AML (86.8+/-13.8%) to MDS (56.8+/-14.3%) and then to normal controls (40.4+/-9.6%) (P<0.01 between each group). In MDS nucleated cells, IGF-IR showed stronger expression in refractory anemia with excess blasts (RAEB)/RAEB in transformation/chronic myelomonocytic leukemia subgroup when compared to RA/RA with ringed sideroblasts cases (64.1+/-3.2 vs 53.5+/-16.2%) (P>0.05). Nucleated cells from MDS marrow underwent more apoptosis (5.4+/-3.0%) than that in normal marrow (1.2+/-0.9%) (P<0.01) and AML marrow (0.3+/-0.4%) (also, P<0.01 between each compared group). For both AML and MDS cases, apoptotic signals presented mainly in individual IGF-IR negative cells (9.0+/-4.8%) and less so in IGF-IR positive cells (1.4+/-2.4%) (P<0.01). When analyzed by groups, cell number with IGF-IR expression showed a negative correlation to apoptotic cells amount (r=-0.852; P<0.01) but positive correlation to their blast count (r=0.677; P<0.01). Outcome from real-time quantitative PCR appeared to have a trend of enhanced IGF-IR expression in advanced MDS subtypes. In conclusion, overexpression of IGF-IR existed in hematopoietic cells in MDS and AML marrows, which appeared to be contributed to disease progress.
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PMID:Expression of type 1 insulin-like growth factor receptor in marrow nucleated cells in malignant hematological disorders: correlation with apoptosis. 1632 78

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