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)

Ineffective hematopoiesis with associated cytopenias and potential evolution to acute myeloid leukemia (AML) characterize patients with myelodysplastic syndrome (MDS). We evaluated levels of apoptosis and of apoptosis-related oncoproteins (c-Myc, which enhances, and Bcl-2, which diminishes apoptosis) expressed within CD34+ and CD34- marrow cell populations of MDS patients (n = 24) to determine their potential roles in the abnormal hematopoiesis of this disorder. Marrow cells were permeabilized and CD34+ and CD34- cells were separately analyzed by FACS to detect: (1) a subdiploid (sub-G1) DNA population, and (2) expression of Bcl-2 and c-Myc oncoproteins. Within the CD34+ subset, a significantly increased percentage of cells demonstrated apoptotic/sub-G1 DNA content in early (ie. refractory anemia) MDS patients compared with normal individuals and AML patients (mean values: 9.1% > 2.1% > 1.2%). Correlated with these findings, the ratio of expression of c-Myc to Bcl-2 oncoproteins among CD34+ cells was significantly increased for MDS patients compared to those from normal and AML individuals (mean values: 1.6 > 1.2 > 0.9). Bcl-2 and c-Myc oncoprotein levels were maturation stage-dependent, with high levels expressed within CD34+ marrow cells, decreasing markedly with myeloid maturation. Treatment of seven MDS patients with the cytokines granulocyte colony-stimulating factor plus erythropoietin was associated with decreased levels of apoptosis within CD34+ marrow cells and may contribute to the enhanced hematopoiesis in vivo that was shown. These findings are consistent with the hypothesis that altered balance between cell-death (eg, c-Myc) and cell-survival (eg, Bcl-2) programs were associated with the increased degrees of apoptosis present in MDS hematopoietic precursors and may contribute to the ineffective hematopoiesis in this disorder, in contrast to decreased apoptosis and enhanced leukemic cell survival in AML.
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PMID:Altered oncoprotein expression and apoptosis in myelodysplastic syndrome marrow cells. 894 64

The relationship between differentiation of human myeloid cells and apoptosis remains unclear. Recent studies have shown that terminal differentiation need not necessarily lead to the apoptotic demise of myeloid cells, while other studies have shown that induction of differentiation is associated with increased resistance to apoptosis-inducing agents, such as chemotherapy and gamma-irradiation. Such results are pertinent to the treatment of acute myeloid leukemia (AML) and myelodysplastic syndrome, where differentiating agents and hemopoietic growth factors are being combined with chemotherapy to enhance response and limit toxicity. To elucidate the factors governing apoptosis in human AML blasts, we have studied the cytotoxic effect of idarubicin on HL60, U937 and KG1 cells, after incubation with all-trans retinoic acid (ATRA), 1, 25(OH)2 D3, and granulocyte-macrophage colony-stimulating factor (GM-CSF ). We show that prior incubation of human myeloid leukemic cells with ATRA or 1,25(OH)2 D3 induced resistance to idarubicin-induced apoptosis, which was modulated by coincubation with GM-CSF. The altered chemosensitivity of cells depended on the degree of G0/G1 cell-cycle arrest induced by incubation with ATRA, 1, 25(OH)2 D3, and GM-CSF and was independent of differentiation status or Bcl-2 oncoprotein expression. These findings suggest that cell-cycle arrest in human leukemic cells can be induced by exogenous agents and may promote drug resistance. Determining the mechanisms by which cell-cycle arrest is induced may permit understanding of the processes by which the cells escape cytotoxic drug-mediated apoptosis.
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PMID:Modulation of idarubicin-induced apoptosis in human acute myeloid leukemia blasts by all-trans retinoic acid, 1,25(OH)2 vitamin D3, and granulocyte-macrophage colony-stimulating factor. 937 69

The major vault lung resistance protein LRP is a cytoplasmic protein involved in drug resistance, especially in acute myeloid leukemia. We looked for LRP overexpression, using immunocytochemistry with LRP 56 monoclonal antibody, on marrow slides from 41 cases of myelodysplastic syndromes (MDS). LRP overexpression (LRP+) was defined by expression of LRP 56 in at least 20% of marrow blasts. LRP overexpression was seen in 19 (46%) cases. Concordant results between LRP overexpression and P-glycoprotein (PGP) expression were seen in 66% of the cases (p = 0.03), and discordant results (LRP+ and PGP-, or LRP- and PGP+) in 33% of the cases. No correlation was seen between LRP overexpression and FAB type, karyotype, CD34, p53 expression and bcl2 overexpression in blasts. Furthermore, in the 18 cases treated with anthracycline-AraC intensive chemotherapy and the 7 cases treated with low dose AraC, the response rate was not significantly different in LRP+ and LRP- patients. Survival was also similar in LRP+ and LRP- patients. In conclusion, LRP overexpression is probably more frequent in MDS than in de novo AML and, as in AML, is only partially correlated with PGP expression. In our experience, however, LRP was not a prognostic factor for response to chemotherapy and survival in MDS.
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PMID:Expression of lung resistance protein and correlation with other drug resistance proteins and outcome in myelodysplastic syndromes. 964 68

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

The NPM-MLF1 chimeric protein is produced by the t(3;5)(q25.1;q34) chromosomal translocation, which is associated with myelodysplastic syndrome (MDS) prior to progression into acute myeloid leukemia (AML). Here we report that K562 human leukemia cells ectopically expressing NPM-MLF1, but not those with wild-type MLF1, were gradually eliminated from the culture by undergoing apoptosis. NIH3T3 mouse fibroblasts engineered to overexpress NPM-MLF1 grew normally but serum deprivation triggered apoptotic cell death with slower kinetics than did other well-known apoptotic inducers such as c-Myc or E2F-1. Quantitative analysis of apoptotic induction confirmed that, neither NPM nor MLF1, but the NPM-MLF1 fusion protein was able to induce apoptosis. Analyses using a variety of deletion mutants of NPM-MLF1 revealed that induction of apoptosis required the N-terminal domain of MLF1 and the NPM domain containing nuclear localization signal and that removal of the NPM dimerization domain markedly impaired the ability to induce apoptosis. Co-expression of Bcl-2 rescued NIH3T3 fibroblasts from NPM-MLF1-mediated cell death without affecting the expression level or the subcellular localization of NPM-MLF1 and enabled cells to progress into S phase in low serum. These findings provide an NPM-MLF1-mediated novel mechanism of apoptotic induction and imply that NPM-MLFI in collaboration with anti-apoptotic oncoproteins may play an important role in multi-step progression from MDS to AML.
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PMID:Apoptosis induced by the myelodysplastic syndrome-associated NPM-MLF1 chimeric protein. 1039 79

P39/Tsugane is a myelomonocytoid cell line derived from a patient with myelodysplastic syndrome (MDS). The cells readily undergo apoptosis in response to various agents, and the cell line has been suggested as a useful model to study apoptosis in MDS. The aims of the present study were to assess differentiation and apoptosis induced with all-trans retinoic acid (ATRA) and etoposide, to characterize the mode of apoptosis in these two model systems, and to assess the influence of granulocyte colony-stimulating factor (G-CSF), which in combination with erythropoietin has been shown to inhibit apoptosis in MDS. ATRA induced differentiation and apoptosis in a concentration- and time-dependent manner. Differentiated cells were partially rescued (by 50%) from apoptosis with G-CSF. Etoposide induced apoptosis in a concentration- and time-dependent manner, but no signs of preceding maturation or G-CSF rescue were detected. ATRA- and etoposide-induced apoptosis were both mediated through the caspase pathway and were partially blocked with the general caspase inhibitor zVAD-fmk. Simultaneous treatment with G-CSF and zVAD-fmk additively blocked ATRA-induced apoptosis. However, the two pathways differed in terms of substrate cleavage during apoptosis. ATRA-induced apoptosis caused actin cleavage, which was not affected by G-CSF, and Bcl-2 downregulation. Etoposide induced a caspase-dependent cleavage of Bcl-2, while actin remained intact. The Fas system did not seem to play a major role in any of these apoptotic pathways. Our results may provide new tools to study the mechanisms of apoptosis in MDS.
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PMID:Two pathways of apoptosis induced with all-trans retinoic acid and etoposide in the myeloid cell line P39. 1042 9

Bone marrow CD34(+) cell apoptosis (annexin V), proliferation (Ki-67), and Bcl-2-related protein expression was evaluated by flow cytometry in 102 patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia secondary to MDS (MDS-AML) and in 30 normal donors (NBM). Apoptosis was significantly increased in refractory anemia (RA)/RA with ringed sideroblasts (RARS) (56.9% [20.4%-93.6%]) and refractory anemia with excess blasts (RAEB) (51.2% [25.2%-76. 6%]) compared with NBM (16.7% [3.4%-35.3%], P <.0001). In RA/RARS, apoptosis always exceeded proliferation (Ki-67-positivity, 26.1% [9.5%-47.8%]; apoptosis:proliferation ratio 2.08 [1.15-3.63]); whereas in RAEB, this ratio equalized (1.14 [0.93-2.08]) due to increased proliferation (40.4% [22%-69.5%]). Progression to RAEB in transformation (RAEB-t)/MDS-AML was associated with a significant reduction in apoptosis (22.3% [2.1%-53.2%]; P <.0001) and proliferation (16.8% [1.9%-75.8%); P =.04; ratio 1.69 [0.16-12.21]). Pro-apoptotic (Bax/Bad) versus anti-apoptotic (Bcl-2/Bcl-X) Bcl-2-related protein ratios were increased in RA/RARS compared with NBM (2.57 [1.93-9.42] versus 1.89 [0.65-4.1]; P =.06), whereas disease progression was associated with significantly reduced ratios (1.16 [0.06-3.32]; P <.0001) due primarily to increased Bcl-2 expression. Apoptosis and Bax/Bad:Bcl-2/Bcl-X ratio were inversely correlated with both International Prognostic Scoring System score and cytogenetic risk group; highest levels observed in patients with low score and/or good risk cytogenetics. There was a trend toward an association between Bcl-2-related protein expression and apoptosis (P =.07). This study indicates that MDS progression arises through multiple hits that alter levels of CD34(+) cell apoptosis and proliferation. Early disease is associated with excessive apoptosis and elevated ratio of apoptosis to proliferation. Increased proliferative rates are observed in RAEB, whereas leukemic transformation arises through inhibition of apoptosis rather than excessive cell growth. Although disease progression is accompanied by a fall in pro-apoptotic versus anti-apoptotic Bcl-2-related protein ratios, heterogeneity in patterns of protein expression indicates that factors additional to Bcl-2 family members play a role in the deregulated apoptosis in MDS. (Blood. 2000;96:3932-3938)
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PMID:The role of apoptosis, proliferation, and the Bcl-2-related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS. 1109 80

This paper introduces novel therapeutic strategies focusing on a molecular marker relevant to a particular hematologic malignancy. Four different approaches targeting specific molecules in unique pathways will be presented. The common theme will be rational target selection in a strategy that has reached the early phase of human clinical trial in one malignancy, but with a much broader potential applicability to the technology. In Section I Dr. Richard Klasa presents preclinical data on the use of antisense oligonucleotides directed at the bcl-2 gene message to specifically downregulate Bcl-2 protein expression in non-Hodgkin's lymphomas and render the cells more susceptible to the induction of apoptosis. In Section II Dr. Alan List reviews the targeting of vascular endothelial growth factor (VEGF) and its receptor in anti-angiogenesis strategies for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In Section III Dr. Bruce Cheson describes recent progress in inhibiting cell cycle progression by selectively disrupting cyclin D1 with structurally unique compounds such as flavopiridol in mantle cell lymphoma as well as describing a new class of agents that affect proteasome degradation pathways.
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PMID:Rational approaches to design of therapeutics targeting molecular markers. 1172 98

Gemtuzumab ozogamicin (Mylotarg) is an immunoconjugate composed of a recombinant humanized murine anti-CD33 antibody linked to calicheamicin, a potent cytotoxic agent. The aim of this review is to summarize ongoing trials with gemtuzumab ozogamicin in combination with chemotherapy in acute myeloid leukemia (AML) patients. The studies include determination of safety and efficacy of gemtuzumab ozogamicin in combination with chemotherapy in previously untreated as well as relapsed and refractory AML patients. These studies also determine gemtuzumab ozogamicin's activity in patients with other CD33+ neoplastic diseases such as myelodysplastic syndrome, acute promyelocytic leukemia, chronic myeloid leukemia, and certain subsets of acute lymphocytic leukemia. Moreover, trials are exploring the use of gemtuzumab ozogamicin with novel targeted agents such as Bcl-2 antisense molecules. Gemtuzumab ozogamicin is associated with an acceptable toxicity profile as a single agent; however, the incidence of veno-occlusive disease remains a concern with the use of gemtuzumab ozogamicin in combination with chemotherapy.
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PMID:Trials with gemtuzumab ozogamicin (Mylotarg) combined with chemotherapy regimens in acute myeloid leukemia. 1197 Jul 67

Excessive apoptosis is implicated in the pathogenesis of myelodysplastic syndromes (MDS). We assessed by flow cytometry the expression of several members of the Bcl-2 family in bone marrow mononuclear cells (BMMNC) of 168 MDS samples at diagnosis. The proteins studied were Bcl-2, Bcl-xL (anti-apoptotic), Bax, Bad, Bak, and Bcl-xS (pro-apoptotic). The percentage of BMMNC expressing Bcl-2 and Bcl-xL was higher in refractory anemia with excess of blasts (RAEB), RAEB in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMML) than in refractory anemia (RA) and RA with ringed sideroblasts (RAS). Conversely pro-apoptotic proteins Bad, Bak, and Bcl-xS were detected in a higher percentage of cells in RA and RAS. RA and RAS were associated with an increased Bcl-xS/Bcl-xL ratio. The expression of anti-apoptotic proteins was also correlated with that of CD34 and P170 and with the percentage of blast cells. Two-color analyses demonstrated that CD34 and Bcl-2 were usually expressed in the same cells. No significant correlation was found with cytogenetic abnormalities. Higher expression of pro-apoptotic Bcl-2-family proteins (Bak, Bad, Bcl-xS) and higher Bcl-xS/Bcl-xL ratio were associated with longer survival and decreased risk of leukemic transformation in univariate analysis, whereas expression of anti-apoptotic proteins was associated with decreased survival. Consequently Bcl-2 proteins expression was well correlated with the International Prognostic Scoring System (IPSS). Our data confirm that the control of apoptosis is deregulated in MDS cells. Moreover, the study of markers such as CD34 (or Bcl-2), Bcl-xL, and Bcl-xS provides additional prognostic information.
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PMID:Expression and prognostic significance of Bcl-2 family proteins in myelodysplastic syndromes. 1211 84


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