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)

All-trans retinoic acid (ATRA) is able to specifically differentiate acute promyelocytic leukemic cells (APL) in short-term culture. Patients with APL achieved complete remission within 1-3 months by a progressive maturation of leukemic cells. The advantages of this differentiation therapy are the rapid disappearance of the bleeding disorders and the absence of aplastic phase avoiding the early deaths occurring in 15-30% of patients with conventional chemotherapy. However, relapses occurred when ATRA alone was maintained. For this reason, a chemotherapy is added after complete remission obtained by ATRA. A pilot study on 27 patients was proposed with the sequential combination of ATRA and chemotherapy. A European trial randomizes conventional therapy to the sequential ATRA-chemotherapy protocol. Retinoic acid receptor (RAR alpha) is rearranged by the specific translocation t(15;17) of APL; a PCR technique was developed in order to ensure the diagnosis and to follow the minimal residual disease. Transfection experiment of the chimaeric gene inhibits the transactivation of the natural RAR. ATRA is able to revert the arrest of maturation perhaps through an increase of the expression of the normal allele of RAR, which could overpass the impairment induced by the chimaeric protein on target responsive elements. One of the steps of the repair is the modulation of programmed cell death (PCD). Bcl-2, a gene involved in the PCD, is modulated in in vitro studies, arguing for the engagement of the cell in the natural death. The beneficial effect of differentiation therapy is probably due to the induction of the natural death of the malignant cell.
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PMID:All-trans retinoic acid (ATRA) therapeutical effect in acute promyelocytic leukemia. 146 48

The expression of Bcl-2 family members was examined in normal and leukemic hematopoietic cells. Immature hematopoietic progenitor cells (CD34+/33-/13-) did not express Bcl-2 but Bcl-XL, the majority of CD34 cells expressed Bcl-2, Bcl-XL and BAD, and normal promyelocytes (CD34-/33+) lacked expression of both Bcl-2 and Bcl-XL, while leukemic CD34+progenitors and promyelocytes expressed these anti-apoptotic proteins. In AML, Bcl-2 expression was higher on CD34+ than on all AML cells, however, expression of Bcl-2 or Bcl-XL did not predict achievement of complete remission. Surprisingly, low Bcl-2 content was associated with poor survival in a group of patients with poor prognosis cytogenetics. The anti-apoptotic BAD protein was found to be expressed in AML, but was phosphorylated in 41/42 samples. Phosphorylation was found at both sites, Ser 112 and Ser 136. During induction chemotherapy, Bcl-2 levels of CD34 cells increased significantly. In the context of evidence for small numbers of leukemic CD34+ cells expressing very high levels of Bcl-2 prior to therapy, this finding is interpreted as a survival advantage of Bcl-2 overexpressing progenitors and rapid elimination of cells with low Bcl-2. Bcl-2 and Bcl-XL were both expressed in minimal residual disease cells. Downregulation of Bcl-2 mRNA and protein was observed by ATRA and the combination of Ara-C, followed by ATRA, resulted in markedly increased cytotoxicity in HL-60 cells, as compared to Ara-C alone or ATRA followed by Ara-C. Implications of these findings for the development of new therapeutic strategies for AML are discussed.
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PMID:Expression of Bcl-2-related genes in normal and AML progenitors: changes induced by chemotherapy and retinoic acid. 1055 66

In this review, we summarize the morphological features and immunophenotypic profile of chronic lymphocytic leukemia (CLL) cells, discuss the value of these investigations as front line diagnostic tests, and emphasize their correlation with the clinical features, disease progression, molecular genetics and pathogenesis of CLL. In CLL, the morphology of the circulating cells is characteristic and typical in the majority of cases. However, 15% of patients, either at diagnosis or during the course of the disease, show atypical morphology reflected by either (1) an increased (> 10%) number of circulating prolymphocytes, designated CLL/PL, or (2) an increased (> 15%) number of circulating lymphoplasmacytic and cleaved cells, designated 'atypical' CLL. There is strong evidence of a close association between atypical morphology (CLL/PL) and atypical (CLL) and clinical features, e.g. disease progression, advanced stage and survival, molecular genetics, particularly trisomy 12, but also the rare cases with t(11;14) or t(14;19), p53 abnormalities, unmutated immunoglobulin (Ig) VH genes and origin of the cell (naive, pregerminal center cell). CLL cells have a distinct immunological repertoire different from that of other lymphoproliferative disorders. The typical CLL phenotype is CD5+, CD23+, FMC7-, weak expression of surface Ig (sIg) and weak or absent expression of membrane CD22 and CD79b. The latter marker identifies an extracellular epitope of the B-cell receptor (BCR) beta chain and its weak or absent expression in CLL may derive from the expression of a truncated form. This, together with the low expression of CD22, might explain the abnormal signal transduction of CLL cells similar to that of anergic B lymphocytes. Because no single marker is specific for CLL, a composite phenotype considering this set of 5 or 6 markers compounded into a scoring system helps to distinguish CLL from the other B-cell malignancies. Immunophenotypic analysis has also been shown to be useful for minimal residual disease detection and adds valuable prognostic information because the expression of certain markers, such as FMC7 or CD38, seems to be associated with a poor outcome. In addition, CLL cells express a variety of Bcl-2 family proteins with a profile that favors inhibition of apoptosis which, together with the interaction with microenvironmental (e.g. stromal) cells and the release of cytokines, explains the long life span and subsequent accumulation of CLL cells in various organs. Despite controversies relating to the expression of adhesion molecules (selectins and integrins) in CLL cells, it appears that some of these molecules do play a role in the pathogenesis, biology and clinical patterns of the disease. In conclusion, morphology and immunophenotype are the two essential investigations, which must be carried out in all cases of CLL. Both provide relevant information in terms of diagnosis, course of the disease, prognosis and pathogenesis.
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PMID:Morphological and immunophenotypic features of chronic lymphocytic leukemia. 1148 29

Bone-marrow minimal residual disease (MRD) causes relapse after chemotherapy in patients with acute myelogenous leukemia (AML). We postulate that the drug resistance is induced by the attachment of very late antigen (VLA)-4 on leukemic cells to fibronectin on bone-marrow stromal cells. We found that VLA-4-positive cells acquired resistance to anoikis (loss of anchorage) or drug-induced apoptosis through the phosphatidylinositol-3-kinase (PI-3K)/AKT/Bcl-2 signaling pathway, which is activated by the interaction of VLA-4 and fibronectin. This resistance was negated by VLA-4-specific antibodies. In a mouse model of MRD, we achieved a 100% survival rate by combining VLA-4-specific antibodies and cytosine arabinoside (AraC), whereas AraC alone prolonged survival only slightly. In addition, overall survival at 5 years was 100% for 10 VLA-4-negative patients and 44.4% for 15 VLA-4-positive patients. Thus, the interaction between VLA-4 on leukemic cells and fibronectin on stromal cells may be crucial in bone marrow MRD and AML prognosis.
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PMID:Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia. 1289 78

This study assessed prevalence, frequency, age and gender distribution and breakpoint locations, and detection method validity for the bcl-2/IgH rearrangement in 204 healthy individuals. For this purpose, both classic two-step, nested, semi-quantitative PCR as well as a newly established sequence-specific, hybridization probe-based real-time quantitative PCR (RQ-PCR) were employed and tested for their sensitivity and specificity for detecting t(14;18) positive cells in healthy blood donors. Interestingly, almost a quarter (24%; 39/204) of all healthy individuals carried the translocation, confirming data of one large prior report [Summers KE, Goff LK, Wilson AG, Gupta RK, Lister TA, Fitzgibbon J. Frequency of the Bcl-2/IgH rearrangement in normal individuals: implications for the monitoring of disease in patients with follicular lymphoma. J Clin Oncol 2001;19(2):420-4]. Regarding presence as well as frequency of the translocation, no correlation to age (mean frequency 2.0:10(4), with a median of <l:10(4), for <40 years, and mean frequency 1.9:10(4), with a median of <l:10(4) for individuals>or=40 years) nor gender was detected. Comparing the two PCR approaches, a 95.1% concordance (194/204) regarding t(14;18) detection was determined for nested and RQ-PCR, with nested PCR being slightly more sensitive (reproducible detection limit l:10(5) cells versus 1:10(4); maximum detection limit l:10(6) versus 1:10(5)). Sequence analysis confirmed individual breakpoints for all samples analyzed (29/29), indicating detection validity for both PCR approaches and ruling out contamination. The breakpoint location distribution pattern appeared to be comparable to the pattern seen with follicular lymphoma (FL) patient collectives. In conclusion, clonal bcl-2/IgH rearrangements are indeed a very frequent observation in healthy individuals, and appear to be independent of age and gender in regard to presence and frequency. This represents a conflicting finding in context of potential biological significance, and presents a potential disruptive factor for minimal residual disease (MRD) monitoring in FL patients. Prospective future trials will have to clarify the biological significance of this important observation.
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PMID:The bcl-2/IgH rearrangement in a population of 204 healthy individuals: occurrence, age and gender distribution, breakpoints, and detection method validity. 1629 48

PCR protocols for immunoglobulin heavy chain (IgH) gene rearrangements amplification make easy the NHL-B identification. In this study we analyzed PCR products by Capillary Electrophoresis (CE) and GeneScan (GS) software, wich offers clear advantages over the conventional methods such as agarose gels (AGGE), characterized by hight rate of false negative and false positive results. We suggested some criteria--not included in previous NHL-B issues--useful to a correct analysis of results in GS. Since 2003, we collected 2,977 samples (2,770 peripheral blood and bone marrow, and 207 tissues) for GS analysis from NHL-B patients. At beginning PCR products were detected by both AGGE and CE. FR2 and FR3 VH regions were amplified by PCR seminested; together with Bcl-6 "housekeeping" gene from the same sample, as marker of DNA quality and PCR efficiency. Bcl-2/IgH and Bcl1/IgH traslocations were also analyzed for follicular and mantle cells lymphomas respectively. Resolution and sensitivity tests, developed with serial diluitions of clonal products in water and in DNA from healthy individuals, showed for GS 1% of resolution limit (3% AGGE) and 0.5% of sensitivity (5% AGGE). Our criteria for correct interpretations of results are: a) use of "house-keeping" gene Bcl-6; b) costant reference scales for hight and molecular weight; c) clonal peak at least twice higher than adiacent peaks; d) position of clonal peak (central or eccentric) as regards to policlonal peaks distributions. e) peaks features for oligoclonal or biallelic rearrangements evaluation. GS is an ideal method for detecting IgH rearrangements and some characteristic traslocations. The precise determination of the size of the PCR product can be used for the minimal residual disease evaluation. Moreover, it allows semi-quantitative resolution of fragments only one base different in size and may be more objective than gel-based methods.
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PMID:[Molecular diagnosis of non-Hodgkin B lymphomas by capillary electrophoresis and Genescan analysis: a molecular pathology laboratory experience]. 1692 87

We investigated whether FNIII14, a 22-mer peptide derived from fibronectin (FN) that potently impairs interaction of FN with beta1-integrin, could overcome cell adhesion-mediated drug resistance (CAM-DR) induced by very late antigen (VLA)-4-to-FN interaction in acute myelogenous leukemia (AML). Two AML cell lines, U937 cells and HL-60 cells, and fresh leukemic cells from six AML patients with high alpha4-integrin expression exhibited CAM-DR to cytosine arabinoside (Ara C) through VLA-4-to-FN interaction, while fresh leukemic cells from two AML patients with low alpha4-integrin expression did not display CAM-DR to Ara C. FNIII14 impaired VLA-4-to-FN interaction and restored sensitivity to Ara C in the CAM-DR leukemic cells. In these CAM-DR leukemic cells, upregulation of Bcl-2, which was induced through the focal adhesion kinase/Akt signal pathway upon VLA-4-to-FN interaction, was inhibited by FNIII14 treatment. In a mouse model of minimal residual disease (MRD) in bone marrow, 100% survival was achieved by combining FNIII14 with Ara C, whereas Ara C alone prolonged survival only slightly. The myelosuppression induced by Ara C was not augmented by the combination of FNIII14 in mouse experiments. Thus, the combination of anticancer drugs and FNIII14 holds promise to eradicate MRD in bone marrow after chemotherapy.
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PMID:Combination therapy of an anticancer drug with the FNIII14 peptide of fibronectin effectively overcomes cell adhesion-mediated drug resistance of acute myelogenous leukemia. 1797 43

Translocation of chromosomes 14 and 18 [t(14;18)] for detection of minimal residual disease in follicular lymphoma patients can be analyzed by nested polymerase chain reaction (PCR) or by quantitative PCR like LightCycler-based assays. We have compared both methods in blood and bone marrow samples of 28 patients enrolled in a clinical study on immunochemotherapy. In 42% of samples, the bcl2-IgH rearrangement was detectable by nested PCR, but not by LightCycler PCR. Nested PCR was able to reveal a significant drop in positive bone marrow or peripheral blood samples after therapy. In contrast, with LightCycler PCR, the detected drop in t(14;18)-positive cells did not reach statistical significance. The majority of patients showed positive results with nested PCR of peripheral blood or bone marrow without any associations to presence or absence of histological bone marrow (BM) infiltration by lymphoma cells. With LightCycler PCR, the numbers of positive cells were higher in samples from patients with BM infiltration of lymphoma cells (1.9 x 10(-2)) compared to samples from patients without involvement (4.08 x 10(-5)). A similar trend was seen in samples derived from the peripheral blood. Positivity for t(14;18) after therapy in two patients correlated with clinical relapse 6 months later. The data shown here demonstrate a lower sensitivity of LightCycler vs. nested PCR for detection of t(14;18). The usefulness of nested PCR for t(14;18) for risk stratification after primary therapy has to be validated in larger trials.
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PMID:Commercial LightCycler-based quantitative real-time PCR compared to nested PCR for monitoring of Bcl-2/IgH rearrangement in patients with follicular lymphoma. 1863 59

Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 protein family. Increased Mcl-1 expression is associated with failure to achieve remission after treatment with fludarabine and chlorambucil in patients with chronic lymphocytic leukemia (CLL). However, the influence of Mcl-1 expression has not been examined in CLL trials using chemoimmunotherapy. We investigated Mcl-1 protein expression prospectively as part of a phase 2 study evaluating the efficacy of pentostatin, cyclophosphamide, and rituximab in patients with untreated CLL. No significant difference by Mcl-1 expression was noted in pretreatment or response parameters. However, in patients with higher Mcl-1 expression, both minimal residual disease-negative status and progression-free survival was found to be significantly reduced (57% vs 19%, P = .01; 50.8 vs 18.7 months; P = .02; respectively). Mcl-1 expression may therefore be useful in predicting poor response to chemoimmunotherapy. These findings further support pursuing treatment strategies targeting this important antiapoptotic protein. (Because the trials described were conducted before the requirement to register them was implemented, they are not registered in a clinical trial database.).
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PMID:Mcl-1 expression predicts progression-free survival in chronic lymphocytic leukemia patients treated with pentostatin, cyclophosphamide, and rituximab. 1900 56

B-cell chronic lymphocytic leukaemia (B-CLL) is characterized by clonal growth and accumulation of mature lymphoid cells due to disturbance in genetically regulated form of cell death called apoptosis. The intrinsic mechanism of apoptosis is controlled by Bcl-2 family proteins. Purine nucleoside analogues induce the apoptosis in cells in a state of quiescence. The aim of the study was to assess expression of selected Bcl-2 family proteins in neoplastic infiltration in bone marrow in patients with B-CLL treated with nucleoside analogues. The study comprised examination of bone marrow obtained routinely by trephine biopsy from 18 patients with B-CLL diagnosed before administration of purine nucleoside analogues treatment and after its completion. Expression of Bcl-2, Bcl-x and Bax proteins was examined. Lymphoid cells in bone marrow were present in all patients before administration of treatment. After treatment in two patients bone marrow was infiltrated in diffuse pattern, whereas other patients presented nodular pattern of infiltration. The difference between stage of infiltration before and after treatment was statistically significant (p<0.002). High percentage of infiltration cells with positive anti Bcl-2 reaction from 42.0% in one patient to 85.33+/-3.06% in four patients before treatment was observed. After treatment percentage of infiltration cells with positive anti Bcl-2 antibody reaction was from 33.0+/-18.38% in two patients to 99.0% in one patient. Positive correlation between stage of infiltration and expression of Bcl-2 protein was confirmed before and after treatment. Such correlations were not observed in case of Bax and Bcl-x. Strong staining of immunohistochemical reaction of cells in lymphoid infiltration with Bcl-2 antibody was confirmed. There was a difference between Bcl-/Bax ratio before and after treatment. Immunohistochemical assessment of expression of Bcl-2 family proteins in cells of lymphoid infiltration in bone marrow of patients with CLL is an important method in detection of minimal residual disease (MRD) after treatment.
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PMID:Assessment of expression of selected Bcl-2 family proteins in lymphoid infiltration in patients with B-cell chronic lymphocytic leukaemia treated with nucleoside analogues. 1905 41


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