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At least 703 records · Page 39Linked to original sources
PubMed2005

COMBO-FISH for focussed fluorescence labelling of gene domains: 3D-analysis of the genome architecture of abl and bcr in human blood cells.

Structural analysis and nanosizing of gene domains requires not only high-resolution microscopy but also improved techniques of fluorescence labelling strongly focussed on the gene domains. To investigate the architecture of abl and bcr in blood cell nuclei forming the Philadelphia chromosome in CML, we applied COMBO-FISH using specifically colocalising combinations of triple strand forming oligonucleotide probes for abl on chromosome 9 and bcr on chromosome 22. Each probe set consisting of 31 homopyrimidine oligonucleotides was computer selected from the human genome database. Measurements by 3D microscopy were compared to results obtained after standard FISH using commercially available abl/bcr BAC probes. The relative radial fluorescence distributions in lymphocyte cell nuclei of healthy donors in comparison to cell nuclei of blood cells of CML patients showed a strong correlation in the location of abl and bcr for both labelling techniques. The absolute distances of the homologous bcr domains and the abl domain-nuclear center-abl domain angles in cell nuclei of CML donors differed significantly from those of healthy donors only when COMBO-FISH was applied. These results indicate that COMBO-FISH may be more sensitive than standard FISH in case of slight modifications in the genome architecture.

Combinatorial Chemistry Techniques↗
PubMed2003

Induced dendritic cell differentiation of chronic myeloid leukemia blasts is associated with down-regulation of BCR-ABL.

Although differentiation of leukemic blasts to dendritic cells (DC) has promise in vaccine strategies, the mechanisms underlying this differentiation and the differences between leukemia and normal progenitor-derived DC are largely undescribed. In the case of chronic myeloid leukemia (CML), understanding the relationship between the induction of DC differentiation and the expression of the BCR-ABL oncogene has direct relevance to CML biology as well as the development of new therapeutic approaches. We now report that direct activation of protein kinase C (PKC) by the phorbol ester PMA in the BCR-ABL(+) CML cell line K562 and primary CML blasts induced nonterminal differentiation into cells with typical DC morphology (cytoplasmic dendrites), characteristic surface markers (MHC class I, MHC class II, CD86, CD40), chemokine and transcription factor expression, and ability to stimulate T cell proliferation (equivalent to normal monocyte-derived DC). PKC-induced differentiation was associated with down-regulation of BCR-ABL mRNA expression, protein levels, and kinase activity. This down-regulation appeared to be signaled through the mitogen-activated protein kinase pathway. Therefore, PKC-driven differentiation of CML blasts into DC-like cells suggests a potentially novel strategy to down-regulate BCR-ABL activity, yet raises the possibility that CML-derived DC vaccines will be less effective in presenting leukemia-specific Ags.

Blast Crisis↗
PubMedDate not supplied

Comparison of three sequential extraction procedures (original and modified 3 steps BCR procedure) applied to sediments of different origin.

The 3 steps sequential extraction procedure proposed by the Standards Measurements and Testing program (SM&T--formerly BCR) of the European Union has been applied for the speciation of metals in sediments. Results obtained by the application of the BCR standardized procedure were compared to those of two four step sequential extraction procedures, which are different from the BCR procedure only for the introduction of an additional step with NaOCl, as 2nd and 3rd step respectively. Five different metals have been taken into consideration: Cd, Cu, Ni, Pb and Zn. The analytical performances of the laboratory have been evaluated using three certified reference materials: the BCR 601 lake sediment for the BCR sequential extraction procedure, PACS-1 and MESS-1 for total metal concentration. Results showed that the efficiency of NaOCl treatment is higher or at least equal to that of H2O2 treatment and that its selectivity is quite satisfying. Moreover the NaOCl treatment doesn't significantly influence the extraction of the easily reducible fraction.

Certification↗
PubMed1989

DNA rearrangement and restriction fragment length polymorphism within the first BCR intron in Philadelphia-positive acute leukemia.

In some patients with Philadelphia (Ph)-chromosome positive acute lymphoblastic leukemias, breakpoints on chromosome 22 are reported to occur within the first BCR intron. To analyze the breakpoints in chromosome 22 of Ph-positive acute leukemia patients without rearrangement of the 5.8 kb bcr, we cloned the 3' part of the first BCR intron using a synthetic DNA probe. During the course of study, we mapped the region of the deletion/insertion of 1 kb that causes a restriction fragment length polymorphism (RFLP) and found a racial difference in the frequencies of the alleles giving rise to this RFLP. Analyses of the patients' samples indicated that breakpoints were located within the 8.5 kb EcoRl fragment of the first BCR intron in two of five Ph-positive acute leukemia patients. The data, together with the previous reports, indicate that breakpoints within this approximately 50 kb intron are widely scattered, in contrast to those confined within the 5.8 kb bcr in chronic myelogenous leukemias.

Acute Disease↗
PubMed2005

Phosphatidylinositol 3-kinase is required for the transcriptional activation of cyclin D2 in BCR activated primary mouse B lymphocytes.

Induction of cyclin D2 is essential for mediating cell cycle entry in B cells activated by BCR cross-linking. In the present study we show that, like B lymphocytes lacking cyclin D2, the p85alpha subunit of phosphatidylinositol 3-kinase (PI3K) or other components of the B cell signalosome, p110delta-null B cells fail to induce cyclin D2 and enter early G1 but not S phase of the cell cycle. The inhibitors of PI3K activity, LY294002 and Wortmannin, also abrogate cyclin D2 induction by BCR cross-linking, confirming that the class IA PI3K is necessary for cyclin D2 induction in response to BCR stimulation. Furthermore, using both p85alpha-null and p110delta-null B cells and inhibitors of PI3K, this study demonstrates for the first time, that BCR cross-linking induces cyclin D2 mRNA expression via transcriptional activation of the cyclin D2 promoter and that this transcriptional activation of cyclin D2 requires PI3K activity. Moreover, we identify a region between nucleotides -1624 and -1303 of the cyclin D2 promoter containing elements responsive to anti-IgM, which are PI3K dependent. Further characterisation of signalling intermediates downstream of the BCR revealed a perturbation of MAPK signalling pathways in p85alpha-null and p110delta-null B cells, and our data suggests that cross-talk exists between the PI3K and JNK pathways.

Androstadienes↗
PubMed2001

Cytokine dependency of human B cell cycle progression elicited by ligands which coengage BCR and the CD21/CD19/CD81 costimulatory complex.

Coengagement of BCR and the C3dg binding CD21/CD19/CD81 costimulatory complex can profoundly reduce the BCR binding threshold for eliciting B cell S phase entry, provided cytokine is present. IL-4 is substantially better than IL-2, IL-13, and TNF-alpha at exhibiting synergy with BCR:CD21 coengaging ligand (anti-IgM:anti-CD21:dextran) in promoting B cell DNA synthesis. Synergy between IL-4 and anti-IgM:anti-CD21:dextran (a) is not explained by the viability-promoting function of IL-4, (b) occurs when the anti-CD21 moiety engages either C3dg binding or non-C3dg binding domains, (c) does not reflect reversal of FcgammaRII-mediated negative regulation, and (d) involves differing temporal requirements for BCR and IL-4R signal transduction during the activation process. The IL-4R signaling pathway appears to synergize directly with the BCR:CD21 signaling pathway(s) in promoting the progression of resting B cells past an early G1 checkpoint, as well as to promote independently the progression of activated B cells past a later G1 to S checkpoint.

Antigens, CD↗
PubMed2000

STAT5-Dependent CyclinD1 and Bcl-xL expression in Bcr-Abl-transformed cells.

Signal transducers and activators of transcription (STATs) are a family of transcription factors that were originally identified as mediators of cytokine-induced gene expression. We and others have recently shown that STAT5 also plays a major role in cellular transformation by the Bcr-Abl oncogene. Here we show that the antiapoptotic bcl-xL gene product and the cell cycle regulator cyclin D1 are targets of STAT5 in Bcr-Abl-transformed cells. In the CML cell line K562 and in BaF3 cells ectopically expressing Bcr-Abl, both the cyclin D1 and bcl-x promoters are highly active. The activity of these promoters can be strongly repressed by cotransfection of a dominant negative (DN) mutant of STAT5. Moreover, the cyclin D1 and bcl-x promoters contain STAT binding sites to which STAT5 constitutively binds in Bcr-Abl transformed cells. These results suggest that STAT5 contributes to transformation by Bcr-Abl by induction of cyclin D1 and bcl-xL expression.

Apoptosis↗
PubMed1997

The immunoreceptor tyrosine-based activation motif of Epstein-Barr virus LMP2A is essential for blocking BCR-mediated signal transduction.

The Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A) blocks B-cell receptor (BCR) signal transduction in EBV-immortalized B lymphocytes in vitro. The cytoplasmic amino-terminal domain of LMP2A contains an immunoreceptor tyrosine activation motif (ITAM). ITAMs consist of paired tyrosine and leucine residues and play a central role in signal transduction of the BCR and the T-cell receptor (TCR). To investigate the importance of the LMP2A ITAM, two EBV recombinants were constructed, each containing a tyrosine-to-phenylalanine point mutation at amino acid 74 or 85 within the ITAM of LMP2A. Tyrosine phosphorylation, calcium mobilization, and induction of BZLF1 expression were no longer blocked in the LMP2A ITAM mutant LCLs following BCR cross-linking. In addition, the Syk protein tyrosine kinase (PTK) was unable to bind LMP2A in unstimulated LCLs infected with either of the LMP2A ITAM mutants. Analysis of Syk phosphorylation before and after BCR cross-linking in the LMP2A mutant ITAM LCLs compared with wild-type EBV LCLs indicates a specific role of the LMP2A ITAM on the LMP2A-mediated negative effect on the Syk PTK. These data indicate the importance of the LMP2A ITAM motif in the LMP2A-mediated block on BCR signal transduction and position the role of the Syk PTK as being central to the function of LMP2A.

Amino Acid Sequence↗
PubMed1996

Regulation of BCR- and PKC/Ca(2+)-mediated activation of the Raf1/MEK/MAPK pathway by protein-tyrosine kinase and -tyrosine phosphatase activities.

Ligation of the B cell Ag receptor (BCR) activates a protein-tyrosine kinase (PTK) and CD45 protein-tyrosine phosphatase (PTPase)-dependent signaling cascade that results in the activation of Ras. This pathway of Ras activation can operate independently of protein kinase C (PKC) activity. Activation of Ras may lead to two distinct Ras-dependent pathways involving either a Raf1/MEK/MAPK module or a MEKK/SEK/SAPK module; however, it is unclear as to how Ras controls the independent activation of either of these pathways. We have used genistein and phenylarsine oxide (PAO) as inhibitors of PTK and PTPase, respectively, to investigate whether they regulate the BCR- and Ca2+/PKC-dependent activation of the Ras/Raf1/MEK/MAPK module. Assays of phosphotransferase activities conducted with Ag (TNP6-OVA)-specific 7.9 murine B lymphoma cells demonstrated that BCR-mediated stimulation of the Raf1/MEK/MAPK module is controlled by PTK and PTPase activities. An elevation in [Ca2+]i was required to optimally activate Raf1 and MEK through the BCR. However, when signaling through the BCR was bypassed by direct stimulation of the Raf1/MEK/MAPK module via a rise in [Ca2+]i and phorbol ester-induced PKC activation, the phosphotransferase activities of Raf1, MEK and MAPK were still regulated in a PTK-dependent manner that was also partially sensitive to the PTPase inhibitor PAO. Thus, at least two alternate routes, i.e. a BCR/PTK/Ras-dependent route and another PKC/Ca(2+)-dependent route, may converge at the level of Raf1 for activation of the Raf1/MEK/MAPK module in B cells.

Animals↗
PubMed2004

Evaluation of the BCR sequential extraction procedure applied for two unpolluted Spanish soils.

The procedure of BCR sequential extraction has been applied to five samples from two unpolluted soils in southern Spain. Total concentrations of different elements have been calculated as the sum of the three fractions of BCR and the residue has been measured for each. Also, a total analysis based on INAA or total-digestion techniques has been performed for the same samples. BCR and total analysis closely agreed for As, Pb and Cd. For Cu, Co, Cr and Zn the comparison of the results did not provide definitive conclusions concerning the capability of BCR in measuring total concentrations. On the other hand, in these cases, a certain correlation was found between the concentrations measured and some soil characteristics, especially the clay, organic-matter and CaCO(3) contents. BCR proved incapable of providing accurate measurements for Ni.

Chemical Fractionation↗
PubMed2004

Molecular interactions regulate BCR signal inhibition by CD22 and CD72.

The inhibitory coreceptors CD22 and CD72 downmodulate B-cell receptor (BCR) signaling and function as a molecular switch, determining whether antigen-stimulated B cells undergo apoptosis or proliferation. These coreceptors carry an intrinsic property for associating with the BCR, and this association is crucial for the initiation of signal inhibition through phosphorylation of these coreceptors by BCR-associated kinases. Recent findings have demonstrated that signal inhibition by these coreceptors is regulated by ligands for the coreceptors and by molecules binding to the coreceptors or the BCR. Moreover, signal inhibition by CD22 depends on the BCR isotype. These findings suggest a dynamic regulation of these coreceptors through molecular interactions on the B-cell surface.

Animals↗
PubMed2001

New views of BCR structure and organization.

Recent work has provided new insights into the stoichiometry of BCR subunits, as well as the organization of the BCR before and after engagement by antigen. On resting cells, the BCR may be pre-assembled into oligomeric receptor complexes that generate a basal level of signaling. After antigen binding, the BCR may be organized into larger receptor arrays that reside in lipid rafts - sites where signaling enzymes are concentrated. The critical role of BCR assembly and organization in B cell function is underscored by the recent findings that this process is altered in many B cell tumors.

Animals↗
PubMed2002

Lipid rafts unite signaling cascades with clathrin to regulate BCR internalization.

A major function of the B cell is the internalization of antigen through the BCR for processing and presentation to T cells. While there is evidence suggesting that lipid raft signaling may regulate internalization, the molecular machinery coordinating these two processes remains to be defined. Here we present a link between the B cell signaling and internalization machinery and show that Src-family kinase activity is required for inducible clathrin heavy chain phosphorylation, BCR colocalization with clathrin, and regulated internalization. An analysis of different B cell lines shows that BCR uptake occurs only when clathrin is associated with rafts and is tyrosine phosphorylated following BCR crosslinking. We therefore propose that lipid rafts spatially organize signaling cascades with clathrin to regulate BCR internalization.

Antigen Presentation↗
PubMed2003

LAT links the pre-BCR to calcium signaling.

SLP-65(-/-) mice display a partial block at the pre-B cell stage of development. Here, we show that LAT is required for the differentiation of SLP-65(-/-) pre-B cells. We show that LAT and SLP-76 are recruited to the pre-BCR and associated with Ig-alpha upon pre-BCR engagement, whereas LAT interaction with SLP-76 is already detected in untreated pre-B cells. Reconstitution of LAT or SLP-65 expression in SLP-65/LAT(-/-) pre-B cells restored their calcium (Ca2+) mobilization capacity, led to downregulation of surface pre-BCR, and induced differentiation to BCR+ cells. Together, our results suggest that the adaptor proteins LAT and SLP-76 are involved in pre-BCR signaling, thereby rescuing arrested murine SLP-65(-/-) pre-B cells.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Engagement of the B-cell antigen receptor (BCR) allows efficient transduction of ZAP-70-positive primary B-CLL cells by recombinant adeno-associated virus (rAAV) vectors.

Engagement of the B-cell antigen receptor (BCR) by crosslinking of the surface immunoglobulin (sIg) homodimer was studied for recombinant adeno-associated virus (rAAV)-mediated gene transfer into B-cell chronic lymphocytic leukaemia (B-CLL) cells. Leukemic cells obtained from 20 patients were stimulated with anti-sIg-directed antibodies and transduced with rAAV vectors coding for enhanced green fluorescent protein (EGFP) (AAV/EGFP) or CD40L (AAV/CD40L). Transduction of B-CLL cells was enhanced after BCR engagement compared to unstimulated controls (P=0.0356). BCR crosslinking induced a significant, dose- and time-dependent upregulation of heparan sulfate proteoglycan (HSPG), the primary receptor for AAV, on B-CLL cells (mean: 38.2 versus 1.7%; P=0.0006). A correlation of HSPG expression after BCR crosslinking with transduction efficiency by AAV/EGFP (P=0.0153) and AAV/CD40L (P=0.0347) was observed. High expression of zeta-associated protein 70 (ZAP-70) in B-CLL cells correlated with a better transduction efficiency by AAV/EGFP (P<0.0001) and AAV/CD40L (P=0.002), respectively: 48 h after transduction of ZAP-70-positive samples, transgene expression was seen in a mean of 33.8% (s.e.m. 3.7%) and 28.9% (s.e.m. 6.7%) of cells, respectively, and could be specifically blocked by heparin, a soluble competitor of HSPG (P<0.0001). In summary, engagement of the BCR on ZAP-70 positive B-CLL cells allows efficient rAAV-mediated gene delivery.

CD40 Ligand↗
PubMed2000

The leukaemic oncoproteins Bcr-Abl and Tel-Abl (ETV6/Abl) have altered substrate preferences and activate similar intracellular signalling pathways.

Inappropriate activation of Abl family kinases plays a crucial role in different human leukaemias. In addition to the well known oncoproteins p190Bcr-Abl and p210Bcr-Abl, Tel-Abl, a novel fusion protein resulting from a different chromosomal translocation, has recently been described. In this study, the kinase specificities of the Bcr-Abl and Tel-Abl proteins were compared to the physiological Abl family kinases c-Abl and Arg (abl related gene). Using short peptides which correspond to the target epitopes in known substrate proteins of Abl family kinases, we found a higher catalytic promiscuity of Bcr-Abl and Tel-Abl. Similar to Bcr-Abl, Tel-Abl was found in complexes with the adapter protein CRKL. In addition, c-Crk II and CRKL are tyrosine phosphorylated and complexed with numerous other tyrosine phosphorylated proteins in Tel-Abl expressing Ba/F3 cells. GTPase analysis with a Ras-GTP-specific precipitation assay showed constitutive elevation of GTP-loaded Ras in cells expressing the leukaemic Abl proteins. The mitogenic MAPK/Erk kinases as well as Akt/PKB, a kinase implicated to negatively regulate apoptosis, were also constitutively activated by both Bcr-Abl and Tel-Abl. The results indicate that the leukaemic Abl-fusion proteins have catalytic specificities different from the normal kinases c-Abl and Arg and that Tel-Abl is capable to activate at least some pathways which are also upregulated by Bcr-Abl.

3T3 Cells↗
PubMed2006

BCR-bound antigen is targeted to exosomes in human follicular lymphoma B-cells.

BACKGROUND INFORMATION: Exosomes are small membrane vesicles secreted by several cell types during exocytic fusion of multivesicular bodies with the plasma membrane. Exosomes from tumour cells can transfer antigens from cell to cell, a property favouring antigen-specific immune responses in vitro and in vivo, and are thus an interesting putative therapeutic tool in human cancers. Exosomes have been well studied in EBV (Epstein-Barr virus)-transformed human B-cell lines; however, biological stimuli regulating exosome secretion quantitatively and/or qualitatively still remain poorly defined. RESULTS: We analysed the effect of the BCR stimulation on exosome release in the human follicular lymphoma B-cell line DOHH2. We found that BCR (B-cell receptor) triggering of DOHH2 cells induced the polarization of CD63(+) MHC class II compartments. Moreover, BCR stimulation increased the release of exosome-associated proteins in the extracellular space. Finally, we found that the BCR was expressed at the surface of exosomes, and could target a bound anti-human IgG to these vesicles. CONCLUSIONS: BCR can modulate the protein content of exosomes upon stimulation, and can target its bound antigen to these vesicles.

ADP-ribosyl Cyclase 1↗
PubMed2004

[An alternative Abl-kinase inhibitor overcomes imatinib resistance mutations of Bcr-Abl oncogenes].

BACKGROUND AND OBJECTIVE: The tyrosinkinase inhibitor Imatinib is active in Philadelphia-positive (Ph+) leukemia. Mutations within the Bcr-Abl kinase domain represent the major cause for clinical resistance toward imatinib. We aimed to examine, whether the alternative Abl Kinaseinhibitor SKI-DV 2 - 43 may be capable of suppressing the growth of cells expressing mutant forms of Bcr-Abl. METHODS: The proliferation of cells expressing wild-type and mutant forms of Bcr-Abl was measured in the presence of imatinib or the pyrido-pyrimidine SKI-DV 2 - 43. RESULTS: The growth of a cell line expressing wild-type Bcr-Abl was suppressed with higher potency in the presence of SKI-DV 2 - 43 when compared to imatinib. Moreover, SKI-DV 2 - 43 effectively suppressed mutant forms of Bcr-Abl that cause imatinib resistance in patients. CONCLUSION: Therefore, alternative Abl kinase inhibitors might play an important role in the future therapy of Philadelphia-positive leukemias.

Animals↗