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)

Early clinical trials of growth factor augmentation of induction chemotherapy for acute myeloid leukemia have yielded variable results. To test the hypothesis that this heterogeneity is a consequence of the pleiotropic effects of growth factors on leukemic cell biology, we measured the effects of in vivo interleukin 3 (IL-3) administration on leukemic cell proliferation and drug sensitivity. Thirty-four patients with acute myeloid leukemia with high-risk features or advanced myelodysplasia received IL-3 as a continuous infusion beginning 3 days prior to chemotherapy and continuing for the duration of intensive induction therapy. Bone marrow cells were studied prior to and after 3 days of IL-3 administration to assess changes in overall and leukemic progenitor cell [leukemia colony-forming unit (CFU-L)] proliferation, and progenitor cell sensitivity to 1-betad-arabinofuranosylcytosine. The median fold increase in overall leukemic cell proliferation in response to IL-3, assessed as expression of the nuclear antigen Ki67 in 28 patients, was 1.2. The median fold increase in percentage of cells in S phase (assessed in 29 patients) was 1.3. Despite the increase in overall cell proliferation in 70% of cases, CFU-L number increased in only 4 of 20 patients successfully studied (median day 4:day 1 ratio of CFU-L number, 0.6). While this suggests possible terminal differentiation of leukemic progenitor cells, expression of CD34, HLA-DR, c-kit, CD15, and CD14 were not consistently affected by the cytokine. 1-betad-Arabinofuranosylcytosine sensitivity of CFU-L increased significantly in 30% of cases, decreased in 30%, and was unchanged in 40%. Changes in overall cell proliferation (Ki67 expression) and CFU-L were independent predictors of change in 1-beta-d-arabinofuranosylcytosine sensitivity; increase in percentage of cells in S phase in response to IL-3 was correlated with attainment of complete remission. While these findings support the concept of cell cycle recruitment, IL-3 has marked pleiotropic effects on proliferation, differentiation, and survival of leukemic progenitors which make the clinical impact of in vivo cytokine administration for individual patients difficult to predict.
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PMID:Impact of in vivo administration of interleukin 3 on proliferation, differentiation, and chemosensitivity of acute myeloid leukemia. 981 85

Mononuclear cells of the bone marrow (BM) of patients in various subgroups of the myelodysplastic syndrome (MDS) were studied by flow cytometry for the expression of myeloid and lymphoid markers both on the surface and in the cytoplasm. A significantly higher percentage of the BM cells of MDS patients reacted with monoclonal antibodies (mAbs) to myeloid antigens (CD13, CD15 and CD33) by cytoplasmic staining as compared with cell surface staining. The percentage of BM cells expressing CD34 was markedly elevated in patients with RAEB-T. A distinct finding in MDS patients was the expression of myeloid antigens on mononuclear BM cells. The proportion of individuals whose mononuclear BM cells were positive for surface reactivity with anti-CD13 and anti-CD33 mAbs was highest among RAEB-T patients while none of the patients with RA expressed these surface antigens. Cytoplasmic staining significantly increased the percentage of CD13+ and CD33+ BM cells among RAEB and RAEB-T patients. The proportion of individuals whose BM cells possessed myeloid antigens was increased by cytoplasmic staining in all subgroups of MDS. The BM of a considerable proportion of RAEB-T and RAEB patients showed cells which coexpressed the CD7 and CD3 lymphoid markers along with the CD13 and CD33 myeloid antigens. The present study indicates the importance of comparative surface and cytoplasmic immunophenotyping with CD13 and CD33 mAbs for the diagnosis of subgroups of MDS. The coexpression of CD3 and CD7 with markers of the myeloid lineage may reflect derangement of the differentiation of pluripotent stem cells characteristic for MDS.
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PMID:Analysis of myeloid and lymphoid markers on the surface and in the cytoplasm of mononuclear bone marrow cells in patients with myelodysplastic syndrome. 981 67

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

We examined the supportive function of stromal cells from patients with refractory anemia (RA) of myelodysplastic syndrome (MDS) on CD34-positive hematopoietic cell proliferation and differentiation using a long-term bone marrow culture (LTMC) system. Primary marrow stromal cells were obtained from 11 MDS RA patients and 12 healthy volunteers, and freshly prepared CD34-positive bone marrow cells from a normal subject were inoculated onto the stroma. There seems to be three broad patterns of hematopoietic cell growth in the LTMCs. In one group, hematopoietic cells were maintained at near normal levels (type A). In the second group, the number of hematopoietic cells increased within the first 5-10 days of culture, but declined to low levels at 15-20 days of culture as compared with normal control (type B). In the third group, the incidence of hematopoietic cells steadily declined from the beginning of the culture (type C). Furthermore, apoptotic change of hematopoietic cells was very frequently observed in cultures with the type C stroma, which were especially defective for supporting CD34 + cell proliferation and differentiation. The expression of CD95 on hematopoietic cells was induced by the type C stroma, however, production of fas ligand by the stromal cells was not observed. These findings suggest a lack of hematopoietic supportive function in some cases of MDS RA and also indicate that there is heterogeneity of stromal function among MDS RA patients.
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PMID:Bone marrow stroma from refractory anemia of myelodysplastic syndrome is defective in its ability to support normal CD34-positive cell proliferation and differentiation in vitro. 1007 Oct 75

We evaluated the effect of SCF on myeloid differentiation by correlating clonogenic potential (as CFU-GM), bone marrow (BM) plasma SCF levels and CD34/c-kit expression in 57 MDS samples. There was a significant correlation between low SCF levels and 'leukemic' in vitro growth, the number of clusters and the colony/cluster ratio. No correlation was found between BM plasma SCF levels, the pattern of growth and CD34+ c-kit+ expression. These data seem to exclude any direct effect of SCF on leukemogenesis, but suggest that low plasma SCF levels may be at least partially responsible for leukemic growth in MDS.
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PMID:Low plasma stem cell factor levels correlate with in vitro leukemic growth in myelodysplastic syndromes. 1007 Oct 80

We describe a case of stable complete remission in a patient with refractory anemia complicated by severe autoimmune hemolytic anemia, achieved with a single high dose (4 g/m2) of cyclophosphamide (cyclo). Concomitantly, an effective mobilization of CD34-positive cells was induced. Other immunosuppressive approaches including high-dose methylprednisolone, high-dose immunoglobulin, and cyclosporine had been ineffective. This finding suggests that, in selected cases, an immunologic mechanism may mediate cytopenia in myelodysplastic syndromes (MDS). In addition, it demonstrates that successful mobilization of peripheral blood stem cells can be induced with high-dose cyclo in MDS.
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PMID:Complete remission of refractory anemia following a single high dose of cyclophosphamide. 1008 24

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

Tetrasomy 8 as a sole anomaly in hematological disorders is relatively rare. To the best of our knowledge, only 19 such cases have been described in the literature to date. Of them, acute myeloid leukemia (AML) in 13 (M1, one; M2, three; M4, one; M5, eight), acute lymphoblastic leukemia(ALL) in one, myelodysplastic syndrome(MDS) in 3, polycythemia vera(PV) and myelofibrosis(MF), one case each. Their median survival was 20 weeks. Here, we report the first case of a 29-year-old man with minimally differentiated AML (AML-M0) displaying a tetrasomy 8 clone. Immunophenotyping showed positivity with CD33, CD34 and intracellular MPO, but all lymphoid markers tested were negative. Conventional cytogenetics of bone marrow cells showed 84.9% of metaphases with tetrasomy 8 in addition to 15.1% with normal diploidy. However, Fluorescence in situ hybridization(FISH) using a centromeric probe specific for chromosome 8 revealed trisomy 8 in 14.2% of interphase nuclei besides tetrasomy 8 in 82.4%. The patient died four weeks after diagnosis without therapy. In conclusion, these findings suggest that tetrasomy 8 is associated with a heterogeneous group of myeloid disorders and heralds a bad prognosis. It may be a consequence of clonal evolution of trisomy 8.
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PMID:Isolated tetrasomy 8 in minimally differentiated acute myeloid leukemia (AML-M0). 1034 86

In order to determine the relationship between bone marrow (bm) endosteal cells (EDC) and hemopoietic progenitors, we have analyzed the immunophenotype of EDC using various antibodies (Ab) against mesenchymal antigens. The Ab were applied on paraffin sections of normal bm (iliac crest, n=17; talus, n=1; phalanx, n=1), myeloregenerative bm (after chemotherapy), and hematologic disorders (acute myeloid leukemia (AML), n=8; chronic myeloid leukemia (CML), n=6; myelodysplastic syndromes (MDS), n=14; severe aplastic anemia (SAA), n=4; essential thrombocythemia (ET), n=2; idiopathic (primary) osteomyelo-fibrosis (IMF), n=1; polycythemia vera (PV), n=1). In normal bm, EDC were found to react with Ab against vimentin, tenascin, alpha-smooth muscle actin, osteocalcin, CD51, and CD56, but did not react with Ab against CD3, CD15, CD20, CD34, CD45, CD68, or CD117. An identical phenotype of EDC was found in AML, MDS, SAA, ET, IMF, PV, myeloregenerative bm, and peripheral bones lacking active hemopoiesis (talus, phalanx). In patients with CML, EDC reacted with Ab to CD51, but did not react with Ab to CD56. Based on their unique antigen profile, EDC were enriched from normal bm by enzyme digestion and cell sorting. However, these enriched cells (CD56+, CD45-, CD34-) did not give rise to hemopoietic cells under the culture conditions used, i.e. in the presence of the growth factors IGF-1, bFGF, SCF, IL-3, and GM-CSF Together, our data do not support the hypothesis that EDC are totipotent mesenchymal progenitors giving rise to hemopoietic cells.
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PMID:Immunophenotypic characterization of human bone marrow endosteal cells. 1039 6

We have previously reported that vitamin K2 (VK2) has a potent apoptosis inducing activity toward various types of primary cultured leukemia cells including acute myelogenous leukemia arising from myelodysplastic syndromes (MDS). We established a novel cell line, designated MDS-KZ, from a patient with MDS in blastic transformation, and further investigated the effects of VK2 using this novel cell line. MDS-KZ shows complex chromosomal anomaly including -4, 5q-, -7, 13q+, 20q-, consistent with that seen in the original patient. Culture of MDS-KZ cells in RPMI1640 medium containing 10% FBS lead to steady but very slow proliferation with a doubling time of 14 days. However, the cellular growth rate was significantly accelerated in the presence of various growth factors such as granulocyte colony-stimulating factor, stem cell factor, granulocyte-macrophage colony-stimulating factor, interleukin-3, and thrombopoietin. Most of the cultured cells show the morphological features of myeloblasts. They are positive for CD7, CD33, CD34, CD45, CD117, and HLA-DR. However, about 10% of the cells are more mature metamyelocytes and neutrophils with various dysplastic characteristics such as pseudo-Pelger nuclear anomaly and hypersegmentation, suggesting a potential for differentiation in this cell line. As previously reported for cultured primary leukemia cells, exposure to VK2, but not to VK1, resulted in induction of apoptosis of MDS-KZ cells in a dose-dependent manner (IC50: 5 microM). In addition, VK2 treatment induced down-regulation of BCL-2 and up-regulation of BAX protein expression with concomitant activation of caspase-3 (CPP32). A tetrapeptide functioning as antagonist of caspase-3, Ac-DEVD-H, suppressed the VK2-induced inhibition of cell growth, suggesting that caspase-3 is, at least in part, involved in VK2-induced apoptosis. These observations suggest that the MDS-KZ cell line can serve as a model for the study of the molecular mechanisms of VK2-induced apoptosis.
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PMID:Vitamin K2 induces apoptosis of a novel cell line established from a patient with myelodysplastic syndrome in blastic transformation. 1048 91


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