Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Myelodysplastic syndromes (MDS) are highly proliferative bone marrow (BM) disorders where the primary lesion presumably affects a CD34+ early progenitor or stem cell. We investigated the proliferative characteristics of CD34+ cells of 33 untreated MDS patients (19 RA, 5 RARS, 7 RAEB, 2 RAEBt) and five patients with acute myeloid leukemia after MDS (sAML). All patients received a 1-h infusion of the thymidine analogue iodoor bromodeoxyuridine intravenously before a BM aspirate and biopsy was taken. A double-labeling immunohistochemistry technique by monoclonal anti-CD34 (QBend/10) and anti-IUdR/BrdU antibodies was developed and performed. By this technique we recognised CD34+ and CD34- cells actively engaged in DNA synthesis or not. As MDS evolves a significant increase occurred in the percentage of CD34+ cells of all myeloid cells (mean value: RA/RARS 1.67%; RAEB(t) 8.68%; sAML 23.83%) as well as in the percentage of proliferating CD34+ cells of all myeloid cells (RA/RARS 0.19%; RAEB(t) 0.43%; and sAML 3.30%). This was associated with a decreasing trend in the overall myeloid labeling index (LI: RA/RARS 25.8%, RAEB(t) 24.6% and sAML 21.5%). This decrease in overall myeloid LI is due to an exponential increase in the proportion of CD34+ cells of the proliferating compartment during MDS evolution (RA/RARS 0.35%, RAEB(t) 1.44% and sAML 11.98% of all S-phase cells). These CD34+ cells appeared to proliferate more slowly than their more mature CD34 negative counterparts, since we found a progressive increment in the mean total cell cycling time (Tc) of all myeloid cells during MDS progression (RA/RARS 39.8, RAEB(t) 45.2 and sAML 65.8 h). This study showed that during MDS evolution to sAML the CD34+ compartment develops a growth advantage leading to apparent expansion.
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PMID:Apparent expansion of CD34+ cells during the evolution of myelodysplastic syndromes to acute myeloid leukemia. 982 42

Apoptosis of peripheral leukocytes in 9 patients with myelodysplastic syndromes (MDS) was examined in vitro, using peripheral blood that had been gently incubated at 37 degrees C for 5 hours. The MDS patients included 3 with refractory anemia, 2 with refractory anemia with ringed sideroblasts, and 4 with refractory anemia with excess blasts. Peripheral blood specimens were also obtained from a control group consisting of 10 patients with iron deficiency anemia (IDA), 10 with idiopathic thrombocytopenic purpura (ITP) and 10 healthy individuals. Apoptotic granulocytes (Apo-Gs) were identified by morphological changes, including nuclear fragmentation, and expressed as a percentage of every 300 granulocytes counted. Apo-Gs were counted 1, 2, 3, 4, and 5 hours after incubation. Although the percentage of apo-Gs climbed over time in the MDS patients, a small number of apo-Gs were also observed in the healthy individuals. In the MDS patients, the proportions of apo-Gs 5 hours after incubation (37 degrees C) were significantly higher than those in the IDA and ITP patients and healthy individuals (15.7 +/- 8.0% in MDS patients vs. 2.8 +/- 1.2% in IDA patients, 2.3 +/- 1.7% in ITP patients, and 0.7 +/- 0.6% in healthy individuals; p < 0.005). No significant differences were observed in the proportions of apo-lymphocytes. DNA fragments were observed in blood lymphocyte from an MDS patient examined. Negative correlations between the percentages of granulocytes and Apo-Gs tended to be observed in the MDS patients. These results suggest that a strong susceptibility to peripheral granulocyte apoptosis is one of possible causes of granulocytopenia in MDS patients.
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PMID:[Apoptosis of peripheral leukocytes in patients with myelodysplastic syndromes]. 986 18

We performed flow cytometric analysis of CD34+ cell apoptosis in 59 patients with myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) secondary to MDS (MDS-AML) using annexin V-FITC, which binds to exposed phosphatidylserine on apoptotic cells. Apoptosis was significantly increased in FAB subtypes RA, RARS and RAEB (<10% blasts) (56.5% (15.1-86.5%)) compared to normal controls (18.5% (3.4-33.4%), P<0.0001) and RAEB-t/MDS-AML (16% (2.1-43.2%), P<0.0001). There was no correlation between % apoptosis, Full blood count or cytogenetics in any disease category. Two-colour cytometric analysis of permeabilized CD34+ cells stained with antibodies to Bcl-2, Bcl-X (anti-apoptotic), Bax and Bad (pro-apoptotic), demonstrated significantly higher ratios of pro- v anti-apoptotic proteins in early MDS (2.47 (1.19-9.42) compared to advanced disease (1.14 (0.06-3.32), P=0.0001). Moreover, using repeated measures of variants (ANOVA), we found that variations between individual Bcl-2-related proteins differed significantly according to disease subtype (P<0.0005). Our results confirm that CD34+ cell apoptosis was significantly increased in MDS subtypes RA and RARS and fell with disease progression. Early MDS was also associated with a significantly higher CD34+ cell pro- v anti-apoptotic Bcl-2-family-protein ratio than advanced disease. Furthermore, patterns of expression of individual Bcl-2 related proteins differed significantly between different disease categories. However, no correlation between pro- v anti-apoptotic Bcl-2-family-protein ratios and the degree of apoptosis was observed.
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PMID:'Low-risk' myelodysplastic syndrome is associated with excessive apoptosis and an increased ratio of pro- versus anti-apoptotic bcl-2-related proteins. 988 23

Fitness landscapes, which provide a unique perspective for viewing co-evolving cell populations, were used to study the evolution of CML and MDS. This led to several conclusions: (1) accelerated phase CML and RAEB/RAEBt are not specific disease entities. They represent the time when AML cells are replacing preleukemia cells; (2) monoclonal hemopoiesis and RA/RARS represent a variety of clinical syndromes with a common appearance but with different evolutionary potential; (3) malignant cells alter the fitness landscape enhancing their proliferative advantage. These studies provide the basis for new approaches to treatment.
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PMID:Fitness landscapes and the myeloid leukemias. 1007 Nov 32

Although it has been known that patients with chronic lymphocytic leukemia (CLL) have a higher frequency of second malignant neoplasms, the development of acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) in these patients is extremely rare. Most reported cases have been therapy-related. In this article, we report the clinical and immunophenotypic features of 5 cases of untreated CLL concurrent with or followed by the development of AML or MDS. All 5 patients were men, with ages ranging from 57 to 87 years (mean, 73.8 years). Four patients had AML and 1 patient had refractory anemia with ringed sideroblasts. In the 4 cases of AML and CLL, 2 distinct cell populations (i.e., myeloblasts and lymphocytes) were identified morphologically and/or immunophenotypically. Our findings support that this rare concurrence of AML or MDS and untreated CLL may represent 2 separate disease processes.
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PMID:Untreated chronic lymphocytic leukemia concurrent with or followed by acute myelogenous leukemia or myelodysplastic syndrome. A report of five cases and review of the literature. 1007 13

Megakaryocytic differentiation of progenitor cells was investigated in nine patients with low-risk myelodysplastic syndromes (MDS) (eight refractor anemia [RA] and one RA with ringed sideroblasts [RARS] and five patients with high-risk MDS (two RA with excess of blasts [RAEB] and three RAEB in transformation [RAEB-T]). Bone marrow-derived CD34+ cells were enriched to a purity of 87% +/- 2% (mean +/- SEM) and assayed in short-term suspension cultures in the presence of 10 ng/mL of PEGylated recombinant human megakaryocyte (MK) growth and development factor (PEG-rHuMGDF) and in addition to 50 ng/mL stem cell factor and 10 ng/mL interleukin-3. Cells of the megakaryocytic lineage were identified by flow cytometric analysis of CD42b (GP1b) and mature MKs by morphologic criteria. Transcription of c-mpl receptor-specific mRNA in the CD34+ cells of these patients was investigated by full-length reverse transcriptase polymerase chain reaction of the p form of c-mpl as well as of the alternative splice product c-mpl k. CD34+ cells from seven healthy bone marrow donors served as controls. Differentiation along the MK pathway was stimulated in five patients with RA. C-mpl mRNA was expressed in the CD34+ cells in all cases. In three low-risk patients the capacity for in vitro MK growth was absent or minimal even though mRNA for c-mpl receptor was detected in the CD34+ cells of this group as well. In patients with high-risk MDS, PEG-rHuMGDF stimulated in vitro MK growth from CD34+ cells in only one of five cases. As in the patients with low-risk MDS, c-mpl mRNA for both c-mpl p and c-mpl k splicing products was detected. These results indicate that the in vitro response to stimulation with c-mpl ligand discriminates between two groups of patients with low-risk MDS and that the observed defect in megakaryocytic development is unrelated to the level of c-mpl expression in both low-risk and high-risk MDS.
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PMID:Characterization of defective megakaryocytic development in patients with myelodysplastic syndromes. 1008

Used as single agents, ATRA, G-CSF, and IFN-alpha have shown a moderate benefit in patients with low-risk MDS, with a response rate of 10%. The aim of the present study was to evaluate the efficacy of a combination of these agents. The effect on hemoglobin (Hb), platelets, and absolute neutrophil count (ANC), as well as on transfusion frequency, was examined in 25 patients with MDS (11 RA, four RARS, eight RAEB, two CMML). The median age was 61 years (range 44-81), and the male/female ratio was 14/11. Treatment consisted of ATRA at 25 mg/m2/day p.o. for months 1, 3, 5, 7, 9, and 11, IFN-alpha at 1.5 MIU twice a week s.c. for 52 weeks, and, in patients with initial ANC <500/microl, G-CSF at 100-480 microg daily s.c. according to the degree of ANC. The duration of therapy was scheduled for 12 months. Two patients achieved ongoing CR (+19 months; +16 months), one patient with RA after 3 months and one with CMML after 7 months of treatment. In all patients, the mean ANC increased significantly from 1400+/-200/microl before the start of therapy to 3500+/-600/microl at the end of treatment (p=0.025). In two patients an increase of Hb was observed, and one patient ceased to require transfusions. In an additional patient with RA and 5q-syndrome, the platelet count normalized following administration of ATRA/IFN-alpha, increasing from 89,000/microl to 293,000/microl. The eight RAEB patients were nonresponders. We conclude that therapy with ATRA, IFNalpha, and G-CSF is effective in approximately 35% of low-risk MDS patients (in this study: six of 17) and may induce complete remission in individual cases.
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PMID:Treatment of patients with low-risk myelodysplastic syndromes using a combination of all-trans retinoic acid, interferon alpha, and granulocyte colony-stimulating factor. 1021 54

Myelodysplastic syndromes (MDS) caused by a clonal hematopoietic stem cell disorder progress to either overt leukemia or cytopenia, which leads to lethal infection or bleeding. Although several clinical trials have attempted to reverse cytopenia by using hematopoietic growth factors (HGF), success has been limited due in part to a limited understanding of the role of HGF in MDS progression. The FLT3 ligand, which binds to and activates the FLT3 receptor, does not have a stimulatory effect on hematopoietic cells, but can synergize with other HGF to support the expansion of both immature and committed progenitors. Using ELISA technology we measured endogenous serum levels in 93 patients with MDS: 29 RA, 1 RARS, 31 RAEB, 23 RAEBt, 9 CMML. 48.3% of RA patients' sera had significantly elevated FLT3 ligand levels ranging from 404 to 5735 pg/ml, whereas none of the RAEB, RAEBt, or CMML patients sera had levels different from controls. No significant correlation was found between FLT3 ligand levels and peripheral blood counts, bone marrow cellularity, age, cytogenetic abnormalities, or survival. Our data suggest that FLT3 ligand levels can be upregulated early in the course of MDS, which may represent an appropriate response to a decreased number of normal progenitors, or alternatively a dysregulated HGF system.
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PMID:Endogenous FLT-3 ligand serum levels are associated with disease stage in patients with myelodysplastic syndromes. 1021 61

The aim of this prospective study was to determine whether treatment with a combination of GM-CSF and erythropoietin (rhEpo) can improve the anemia associated with low risk myelodysplastic syndrome (MDS), namely refractory anemia (RA), RA with ring sideroblasts (RAS), and RA with excess of blasts (RAEB) with bone marrow blasts less than 10%. Eligibility criteria included an Hb level of less than 10.5 g/dl for newly diagnosed patients, or symptomatic anemia. GM-CSF was given at a dose of 3 microg/kg s.c. on days 1-2, rhEpo at a dose of 60 U/kg s.c. on days 3-5. No treatment was given on days 6-7. Patients were followed-up with full blood count on a weekly basis. The treatment was repeated for a total of 6 weeks. At that time, if a rise in Hb above 1.5 g/dl had not been achieved, the dose of rhEpo increased to 120 U/kg. Post-treatment evaluation was performed at the completion of 12 weeks. Erythroid response was defined as good (GR), if an increase in untransfused Hb values above 2 g/dl or a 100% decrease in red blood cell transfusion requirements, over the treatment period was observed, while an increase in untransfused Hb values 1-2 g/dl or a >50% decrease in transfusion requirements, were considered as partial response. Responders continued to receive the same treatment until disease progression. Nineteen patients (13 male and six female) with a median age of 69 years were enrolled in the study. The FAB subtypes were: RA one case, RAS eight cases and RAEB 10 cases. Ten of 19 patients (52.6%) responded to the treatment: 7/19 (36.8%) achieved a GR and 3/19 (15.8%) a PR. Six of eight (75%) patients with RAS, one case with RA and 3/10 (30%) of cases with RAEB responded to treatment. Pretreatment serum epo levels were generally low (less than 200 Mu/ml) in responding patients. At the completion of the initial 12 weeks, 8/12 responding patients (5 RAS, 2 RAEB and 1 RA) continued to receive the same treatment. All responding patients with RAS continued to show an erythroid response in a time period from 3 to 24 months, whilst one patient with RA and two with RAEB did not have a continuing response at 2, 4 and 12 months, respectively. The above data suggest that the combination of rhEpo and GM-CSF should be recommended in all cases with RARS. However, the clear indication of this combination for other patients with MDS remains to be determined.
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PMID:Treatment of anemia in low risk myelodysplastic syndromes with granulocyte-macrophage colony-stimulating factor plus recombinant human erythropoietin. 1040 Apr 15

Three pediatric patients with refractory anemia with ringed sideroblasts (RARS) are presented. Bone marrow aspirates were examined using Romanowsky and Prussian blue iron stains in all three patients, and electron microscopic analysis was performed in one patient. All three patients had cytogenetic analysis of the bone marrow. Other studies included analysis of serum iron, total iron-binding capacity, ferritin, copper, vitamins B6 and B12, and folate levels. Antibody titers to Parvovirus, HIV, and other viruses were measured. The patients had contrasting clinical courses. Patients 1 and 2 had dysplastic hematopoietic features and cytogenetic findings (with either partial or one allele loss of chromosome 7), suggestive of myelodysplastic syndrome. Patient 1 experienced acute myeloid leukemia (AML) and had a good response to AML-directed therapy. Patient 2 had prolonged cytopenias and underwent bone marrow transplantation (BMT). Patient 3 had features suggestive of refractory anemia associated with mitochondrial cytopathy, including normal cytogenetics with pronounced vacuolization of marrow precursors. His anemia regressed spontaneously a few months after diagnosis. These patients represent two subgroups of pediatric RARS. Patients with the myelodysplastic syndrome (MDS) type may progress to cytopenias or leukemia and may require aggressive therapy; the type is characterized by clonal cytogenetic findings. The non-MDS type, which may relate to mitochondrial cytopathy, often shows spontaneous regression and requires only supportive treatment; it has normal cytogenetic findings.
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PMID:Refractory anemia with ringed sideroblasts in children: two diseases with a similar phenotype? 1052 57


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