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)

P-glycoprotein (P-gp) is often expressed (40-50%) on leukemic cells at diagnosis in acute myelogenous leukemia (AML), and is even more frequently present after treatment failure. Several large cohorts of newly diagnosed AML patients treated with a classical anthracycline + standard doses of cytosine arabinoside were tested for the prognosis value of MDR1 phenotype, and demonstrated an high correlation between a significant increase of MDR1 gene expression and treatment failure (or, better, drug resistance). This P-gp(+) drug resistance could be due either to a particular phenotype of bad prognosis AML, as it is suggested by the association of myelodysplasia, complex karyotype and advanced age with MDR1 phenotype, or due primarily to the active efflux of anthracyclines and VP16 in P-gp(+) leukemic cells. Several observations tend to confirm the functional role of the P-gp in clinical drug resistance; (i) using multivariate analysis, MDR1 phenotype appears to be an independent variable, as potent (or higher) as karyotype and age for predicting in vivo drug resistance; (ii) the prognostic value is limited to the CD34(+)/P-gp(+) phenotype, wich is linked to a functional P-gp; (iii) the in vitro sensitivity to anthracyclines and VP16 is highly correlated with P-gp expression. All these data argue for an early use of P-gp modifier agents in the treatment of AML. The role of the MDR1 gene in ALL resistance is controversial and marginal compared to the sensitivity of ALL blasts to glucocorticoids, and the frequency of MDR1 phenotype is low at diagnosis, and is increasing only after repetitive chemotherapies.
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PMID:MDR1/P-GP expression as a prognostic factor in acute leukemias. 1050 Jul 74

Apoptosis has been implicated in the pathogenesis of marrow failure in MDS and the coexistence of marrow hypercellularity along with blood cytopenias was seen as evidence of extreme cell death of mainly mature cells in the marrow (ineffective hematopoiesis). We investigated apoptosis in 53 patients with MDS, by using single-step DNA extraction and gel electrophoresis and then by separating fresh marrow mononuclear cells in CD34+ and CD34- populations and in situ single cell evaluation of the process. We also studied the expression of apoptosis-related genes, in total and separated mononuclear marrow cells and correlated the findings with clinical and laboratory characteristics. Patients with apoptosis had increased marrow cellularity, longer overall survival and a longer period for transformation to AML. In 'good' prognosis MDS patients, total mononuclear marrow cells, as well as isolated populations of CD34+ and CD34- cells showed significant degrees of apoptosis; in 'poor' prognosis cases, however, apoptosis was evident only in a large percentage of CD34+ marrow cells and not in total or CD34- cells. Absence of expression of both c-myc and p53 in total marrow cells was associated with significant degrees of apoptosis and in isolated CD34+ and CD34- marrow cells the phenomenon was inversely correlated with the level of bcl-2 expression. In conclusion, marrow apoptosis is detected in both CD34+ and CD34- cells in early MDS and seems to be restricted to CD34+ cells in advanced MDS cases.
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PMID:Apoptosis in patients with myelodysplastic syndromes: differential involvement of marrow cells in 'good' versus 'poor' prognosis patients and correlation with apoptosis-related genes. 1051 57

High-dose melphalan (200 mg/m2) followed by one or more autologous peripheral blood stem cell transplantations is a safe and effective treatment regimen for multiple myeloma. This treatment regimen is as effective as standard therapy for myeloma in older (>65 years) patients and in patients with renal failure. However, advanced age (>50 years), duration of prior standard therapy (> 12 months), and a low CD34 mobilization potential (<20 x 10(6)/kg) are associated with a higher incidence of cytogenetic myelodysplasia. Future efforts directed at curing multiple myeloma should incorporate the best remission induction regimens presently available and should use consolidation/maintenance treatment (eg, idiotype/dendritic cell vaccination and dexamethasone/cyclophosphamide/etoposide/cisplatin combination chemotherapy) to enhance sustained complete remission. Other options to improve the treatment of myeloma include novel adjunctive therapies that target the myeloma cell microenvironment (eg, bisphosphonates, thalidomide, other antiangiogenesis agents) and allogeneic transplantation techniques to induce a graft-versus-myeloma effect.
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PMID:Novel approaches in myeloma therapy. 1052 92

Shwachman-Diamond syndrome (SD), an inherited disorder with varying cytopenias and a marked tendency for malignant myeloid transformation, is an important model for understanding genetic determinants in hematopoiesis. To define the basis for the faulty hematopoietic function, 13 patients with SD (2 of whom had myelodysplasia with a clonal cytogenetic abnormality) and 11 healthy marrow donors were studied. Patients with SD had significantly lower numbers of CD34(+) cells on bone marrow aspirates. SD CD34(+) cells plated directly in standard clonogenic assays showed markedly impaired colony production potential, underscoring an intrinsically aberrant progenitor population. To assess marrow stromal function, long-term marrow stromal cell cultures (LTCs) were established. Normal marrow CD34(+) cells were plated over either SD stroma (N/SD) or normal stroma (N/N); SD CD34(+) cells were plated over either SD stroma (SD/SD) or normal stroma (SD/N). Nonadherent cells harvested weekly from N/SD LTCs were strikingly reduced compared with N/N LTCs; numbers of granulocyte-monocyte colony-forming units (CFU-GM) derived from N/SD nonadherent cells were also lower. SD/N showed improved production of nonadherent cells and CFU-GM colonies compared with SD/SD, but much less than N/N. Stem-cell and stromal properties from the 2 patients with SD and myelodysplasia did not differ discernibly from SD patients without myelodysplasia. We conclude that in addition to a stem-cell defect, patients with SD have also a serious, generalized marrow dysfunction with an abnormal bone marrow stroma in terms of its ability to support and maintain hematopoiesis. This dual defect exists in SD with and without myelodysplasia.
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PMID:Shwachman-Diamond syndrome: An inherited preleukemic bone marrow failure disorder with aberrant hematopoietic progenitors and faulty marrow microenvironment. 1055 88

We scored absolute numbers of circulating CD34+ cells by a highly sensitive triple-color flow cytometric analysis using CD45 monoclonal antibody, CD34 monoclonal antibody and propidium iodide. Forty-one patients with MDS (RA: 27, RARS: 1, RAEB: 6, RAEB-t: 3,CMML: 4), 12 patients with aplastic anemia (AA) and 36 age-adjusted normal subjects were studied. RA had significantly decreased numbers of cells expressing CD34 (0.21 +/- 0.29 x 10(6)/l) compared with normal subjects (0.81 +/- 0.36 x 10(6)/l)(P < 0.001). This low number of CD34+ cells in RA resembles the case of AA (0.39 +/- 0.73 x 10(6)/l). In light-scatter analysis, the CD34+ cells of RA patients were distributed mainly in low forward scatter (FSC) (lymphocyte region). In contrast, the CD34+ cell counts were extremely high in patients with RAEB (46.54 +/- 71.37 x 10(6)/l) and RAEB-t (57.00 +/- 52.36 x 10(6)/l) (P < 0.001) and the CD34+ cells were observed in high FSC (blast region).CMML patients showed moderately increased numbers of CD34+ cells (3.69 +/- 4.64 x 10(6)/l). Thus, there was a distinct difference in cell size and number of circulating CD34+ cells between RA and RAEB/RAEB-t. In univariate and multivariate analysis, a high CD34+ cell count (> or = 1.0 x 10(6)/l) was a poor prognostic factor. This method allows one to distinguish RA from other MDS subtypes more reliably than by morphology alone and provides early signs of progression to acute leukemia.
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PMID:Absolute number of circulating CD34+ cells is abnormally low in refractory anemias and extremely high in RAEB and RAEB-t; novel pathologic features of myelodysplastic syndromes identified by highly sensitive flow cytometry. 1065 53

Refractory anemia (RA) in myelodysplastic syndrome (MDS) without prominent dysplasia closely resemble the mild type of aplastic anemia (AA) in their hematological features. This sometimes makes it difficult to distinguish clearly between the two diseases. Using the multi-color flow cytometric technique, we compared cell surface antigen expression patterns on bone marrow hematopoietic progenitor cells which were isolated as a CD34 positive- CD45 dull positive with low side scatter intensity (CD34(+)CD45(dull+)SSC(low)) population in flow cytogram between RA (n=12) and AA (n=11). The antigens analyzed in CD34(+)CD45(dull+)SSC(low) mononuclear cells were: CD38 and CD71 for cell growth-related antigens, CD 33 and CD13 for myeloid and monocytoid lineage-associated antigens, CD7 and CD19 for lymphoid lineage, and CD14 for a monocytic lineage specific antigen. The percentages of CD34(+)CD45(dull+)SSC(low) cells in bone marrow non-erythroid mononuclear cells, and the expression frequencies of CD38, CD71, CD33 and CD13 antigens in CD34(+)CD45(dull+)SSC(low) progenitors were all significantly decreased in AA compared to normal bone marrows (n=7) (P<0.005). In contrast, in RA bone marrows the percentages of CD34(+)CD45(dull+)SSC(low) cells showed wide distribution and the cell surface antigen expression patterns varied among each case: some cases showed low frequencies of CD38 and CD71 expression as well as AA, whereas the others showed high expression frequency of specific antigen(s) which may reflect the clonal expansion of an abnormal clone in bone marrow. An MDS patient who had progressed from RA to RAEB showed further projecting pattern of expression of CD38 and CD33 in CD34(+)CD45(dull+)SSC(low) population in accordance with the disease progression. These data suggest that analysis of cell surface antigen expression patterns of CD34(+)CD45(dull+)SSC(low) progenitor cells by multi-color flow cytometry appears to be a useful method for qualitative and quantitative assessment of marrow progenitor states in AA and RA, therefore this method could be helpful for early detection of clonal evolution in MDS.
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PMID:Comparative multi-color flow cytometric analysis of cell surface antigens in bone marrow hematopoietic progenitors between refractory anemia and aplastic anemia. 1086 34

A 75-year-old woman presenting with myelodysplastic syndrome showed cyclic oscillations in her white blood cell and platelet counts. Each cycle lasted for 5 to 6 months, with 4 cycles occurring over the course of a 2-year period. During successive cycles, the white blood cell count fluctuated from 10.1 to 2.6; 13.8 to 1.8; 11.0 to 1.6, and 8.6 to 1.3 x 10(9)/L. The platelet count fluctuated from 242 to 38, 199 to 11, 110 to 5, and 75 to 3 x 10(9)/L. The patient underwent red blood cell transfusions because of red blood cell aplasia; the frequency of the transfusions and the erythropoietin concentration in serum were inversely correlated. The number of circulating granulocyte-macrophage colony-forming units and CD34-positive cells in peripheral blood oscillated in phase with the white blood cell and platelet counts. These patterns suggested a periodic influx of progenitor cells from hematopoietic stem cells. The ratio of neutrophils to mononuclear cells remained essentially constant throughout the clinical course. Lymphocyte subset assessments using monoclonal antibodies showed an inverse CD4/CD8 ratio (less than 1) and extreme B cell lymphopenia throughout the fourth cycle. The percentage of CD3-positive cells oscillated inversely, suggesting that the cyclic cytopenia had an immune mechanism involving T lymphocytes.
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PMID:Adult onset cyclic hematopoiesis in a patient with myelodysplastic syndrome. 1072 92

Interstitial deletion or loss of chromosome 5 is frequent in malignant myeloid disorders, including myelodysplasia (MDS) and acute myeloid leukemia (AML), suggesting the presence of a tumor suppressor gene. Loss of heterozygosity (LOH) analysis was used to define a minimal deletion interval for this gene. Polymorphic markers on 5q31 were identified using a high-resolution physical and radiation hybrid breakpoint map and applied to a patient with AML with a subcytogenetic deletion of 5q. By comparing the DNA from leukemic cells to buccal mucosa cells, LOH was detected with markers D5S476 and D5S1372 with retention of flanking markers D5S500 to D5S594. The D5S500-D5S594 interval, which covers approximately 700 kb, thus represents a minimal localization for the tumor suppressor gene. Further refinement of the physical map enabled the specification of 9 transcription units within the encompassing radiation hybrid bins and 7 in flanking bins. The 9 candidates include genes CDC25, HSPA9, EGR1, CTNNA1, and 5 unknown ESTs. Reverse-transcription polymerase chain reaction confirms that all of them are expressed in normal human bone marrow CD34(+) cells and in AML cell lines and thus represent likely candidates for the MDS-AML tumor suppressor gene at 5q31.
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PMID:Delineation of a minimal interval and identification of 9 candidates for a tumor suppressor gene in malignant myeloid disorders on 5q31. 1073 9

The significance of terminal deoxynucleotidyl transferase (TdT) expression in acute myelogenous leukemia (AML) remains controversial. Therefore, we studied TdT expression by flow cytometry in 120 previously untreated patients with AML or myelodysplastic syndrome (MDS) to determine the distribution of TdT-positive blasts and the intensity of TdT expression and to seek clinically significant associations. TdT expression measured by flow cytometry (flow TdT%) was heterogeneous, ranging from 0.1% to 87% (median, 8.5%), and 74 patients (62%) had at least 5% TdT-positive blasts. TdT positivity was associated with the M0 or M1 subtype and with expression of CD34 and CD7. No significant correlation was found between TdT expression and type of cytogenetic abnormality or rearrangement of immunoglobulin or T-cell receptor genes. Remission lasted longer in patients with a flow TdT% < 5 than in patients with a flow TdT% > 5 (median, 95 weeks vs 55 weeks, p = 0.02); however, complete remission rates did not differ when patients were classified by initial flow TdT%. Survival was slightly better for patients with flow TdT% less than 5%. Among patients with a flow TdT% > 5%, those with a higher TdT intensity survived longer than those with a lower intensity. These data suggest that quantitative TdT measurement may contribute to prognostic estimate in AML patients.
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PMID:Terminal deoxynucleotidyl transferase expression in acute myelogenous leukemia and myelodysplasia as determined by flow cytometry. 1075 83

The mechanism of action of antithymocyte globulin (ATG) in the treatment of aplastic anaemia (AA) and myelodysplastic syndromes (MDS) is poorly understood and may involve many different mechanisms. The aim of this in vitro study was to investigate further the effect of ATG on haemopoietic progenitor cells. A total of 16 patients (10 AA and 6 MDS) and 12 normal control subjects were studied. Purified bone marrow (BM) CD34+ cells were cultured in committed progenitor assay in the presence of ATG and autologous serum, then scored on day 14 for granulocyte-monocyte colony-forming units (CFU-GM) and erythroid colonies. ATG was found to be inhibitory to haemopoietic progenitor cells at high concentrations (1000 microg/ml and 100 microg/ml). This was confirmed by CD34-FITC and 7AAD staining of purified normal CD34+ cells after overnight incubation with ATG. In contrast, at lower doses (0.1-10 microg/ml), ATG produced an increase in colony growth in most normal, MDS and AA BM CD34+ cells. The greatest effect was in patients with non-severe AA, in whom the greatest increase in CFU-GM was seen at 0.5 microg/ml (P < 0.02) and 0.1 microg/ml (P = 0.02) and erythroid colonies at 0.1 microg/ml (P < 0.05). Serum ATG levels peaked during infusion to levels that were found to be toxic to haemopoietic progenitor cells in vitro and fell thereafter to levels that were associated with the highest colony numbers (0.1 and 0.5 microg/ml) in vitro. These results suggest that an increase in haemopoietic progenitor cells by ATG may be one of several important mechanisms for haematological recovery in AA and MDS.
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PMID:Effects of antithymocyte globulin on bone marrow CD34+ cells in aplastic anaemia and myelodysplasia. 1075 17


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