Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10415 (Bcl-2)
 33,771 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

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

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

Excessive apoptosis has a central role in ineffective hematopoiesis in myelodysplastic syndrome (MDS). The aim of the study was to quantify apoptosis and Bcl-2 expression in patients with MDS and to use these parameters in the evaluation of treatment efficacy with compounds modulating proapoptotic cytokines. Bone marrow (BM) samples from eight MDS patients were studied: four with refractory anemia and four with refractory anemia with ringed sideroblasts. Two patients with Hodgkin disease without BM determination were studied for control. Therapy consisted in administration of pentoxyphylline, dexamethasone and ciprofloxacin. Biochemical assay of apoptosis and Bcl-2 was performed using annexin V-biotin conjugate antibody and anti-human Bcl-2 antibody respectively, followed by streptavidine-peroxidase conjugate, and peroxidase substrate. Ultrastructural investigation of BM samples was performed with standard electron microscopy techniques. Most of BM hematopoietic cells in the MDS patients had ultrastructural features of various stages of apoptosis including chromatin condensation and margination, cytoplasm condensation and budding of nuclear and plasma membranes to produce apoptotic bodies. Bcl-2 expression showed an inverse correlation with the rate of the apoptotic process. Periodic evaluation of these two parameters has shown an increase of Bcl-2 expression and a decrease of apoptotic rate in patients who had responded to the treatment. Response to the treatment was appreciated in accordance with their transfusion needs. Treatment efficiency diminished in time. The rate of apoptosis was inversely correlated with the level of Bcl-2 expression. These results confirm the importance of the apoptotic process evaluation in monitoring MDS treatment.
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PMID:Apoptotic rate in patients with myelodisplastic syndrome treated with modulatory compounds of pro-apoptotic cytokines. 1459 56

Tumor necrosis factor (TNF)-alpha, a potent stimulus of nuclear factor-kappaB (NF-kappaB), is up-regulated in myelodysplastic syndrome (MDS). Here, we show that bone marrow mononuclear cells (BMMCs) and purified CD34+ cells from patients with low-grade/early-stage MDS (refractory anemia/refractory anemia with ring sideroblasts [RA/RARS]) have low levels of NF-kappaB activity in nuclear extracts comparable with normal marrow, while patients with RA with excess blasts (RAEB) show significantly increased levels of activity (P = .008). Exogenous TNF-alpha enhanced NF-kappaB nuclear translocation in MDS BMMCs above baseline levels. Treatment with arsenic trioxide (ATO; 2-200 microM) inhibited NF-kappaB activity in normal marrow, primary MDS, and ML1 cells, even in the presence of exogenous TNF-alpha (20 ng/mL), and down-regulated NF-kappaB-dependent antiapoptotic proteins, B-cell leukemia XL (Bcl-XL), Bcl-2, X-linked inhibitor of apoptosis (XIAP), and Fas-associated death domain (FADD)-like interleukin-1beta-converting enzyme (FLICE) inhibitory protein (FLIP), leading to apoptosis. However, overexpression of FLIP resulted in increased NF-kappaB activity and rendered ML1 cells resistant to ATO-induced apoptosis. These data are consistent with the observed up-regulation of FLIP and resistance to apoptosis with advanced MDS, where ATO as a single agent may show only limited efficacy. However, the data also suggest that combinations of ATO with agents that interfere with other pathways, such as FLIP autoamplification via NF-kappaB, may have considerable therapeutic activity.
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PMID:NF-kappaB and FLIP in arsenic trioxide (ATO)-induced apoptosis in myelodysplastic syndromes (MDSs). 1610 82