SEARCH · PubMed Health

Results for “BCR”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 109 records · Page 6Linked to original sources

PubMed1990

[Philadelphia chromosome positive acute mixed lineage leukemia with bcr (M-BCR-1) rearrangement].

We report two cases of Philadelphia (Ph1) chromosome positive acute mixed lineage leukemia (AMLL) with breakpoint cluster region (bcr) (M-BCR-1) rearrangement. A 31 year-old-man (case 1) and a 42 year-old-woman (case 2) were admitted to our hospital for further evaluation of leucocytosis with atypical blasts. Each case was diagnosed as having bilineal type of AMLL because: (1) blasts in each case consisted of larger myeloid cells positive for myeloperoxidase and small lymphoid cells positive for PAS, and blasts in case 2 were positive for TdT; (2) blasts in case 1 expressed B lymphoid associated antigen; (3) Southern analysis in each case showed clonal rearrangements of both the immunoglobulin heavy chain and the T cell receptor beta gene. These two cases demonstrated the Ph1 chromosome and rearrangement of the bcr (M-BCR-1) gene, but none of splenomegaly, basophilia, and additional chromosome abnormalities were observed. In addition, after achieving remissions, they didn't revert to chronic phase of chronic myelogenous leukemia (CML) and showed normal neutrophil alkaline phosphatase scores, and the Ph1 chromosome disappeared completely in case 1 and coexisted with the normal chromosome in case 2. These findings suggest that diagnosis of both cases should not be CML blast crisis (BC) but Ph1 positive acute leukemia, and Ph1 positive AMLL may be a distinct clinical entity to be distinguished from CML-BC.

Adult↗

PubMed2005

Interpretation of submicroscopic deletions of the BCR or ABL gene should not depend on extra signal-FISH: problems in interpretation of submicroscopic deletion of the BCR or ABL gene with extra signal-FISH.

Several groups have demonstrated that a submicroscopic gene deletion in Ph+ chronic myelogenous leukemia (CML) is associated with a poor prognosis and reduced response to treatment. To assess the variation between detection methods in the interpretation of a submicroscopic gene deletion, we performed an extra signal (ES)-FISH BCR/ABL and double-FISH (D-FISH) BCR/ABL on frozen bone marrow cells from 79 patients with CML (63 in the chronic phase, 6 in the accelerated phase, and 10 in blast crisis) and 30 patients with a BCR/ABL-negative myeloproliferative disorder as determined by RT-PCR. The normal cutoff values were 0.22% for ES-FISH and 0.25% for D-FISH. The cutoff values for false-positive signals from a juxtaposition of the BCR and ABL gene were 11% in ES-FISH and 13% in D-FISH. Of the 14 patients who showed an ABL gene deletion by ES-FISH, 5 had an ABL deletion only, 5 had both a BCR and an ABL deletion, but 4 proved to have a classic BCR/ABL rearrangement without a submicroscopic deletion, as determined by D-FISH. Discrepant results between ES- and D-FISH were observed in 12 of the 79 patients (15.8%), and the main causes of a discrepancy were a false-positive ABL deletion (4 of 12, 33%), a variant Philadelphia chromosome (3 of 12, 25%), an inversion of derivative chromosome 9 at the very breakpoint of the ABL gene (9q32) (1 of 12, 8.3%), a cryptic variant Ph chromosome (1 of 12, 8.3%), and a marker chromosome (1 of 12, 8.3%). Although there was no significant difference in the sensitivity for the detection of the fusion signal between ES- and D-FISH, ES-FISH showed a high percentage of cells with false-positive fusion signals (1 orange, 1 green, 1 yellow), which makes it difficult to interpret the submicroscopic ABL deletion. In conclusion, an interpretation of the submicroscopic deletions of the BCR or ABL gene should not depend on ES-FISH.

Bone Marrow↗

PubMed1996

BCR gene recombines with genomically distinct sites on band 11Q13 in complex BCR-ABL translocations of chronic myeloid leukemia.

We have analysed a cloned 11q13/3'BCR junction fragment, one recombination product of a complex t(9;11;22) translocation in a patient with chronic myeloid leukemia. 3'M-Bcr recombined with chromosome band 11q13 at a specific point between two Alu elements lying in opposite orientation. We present new molecular data comparing the genomic location of the 11q13 breakpoint in our patient with that of one other recently reported to lie within the GSTP1 gene. This is the first time that specific breakpoint sites within a chromosomal region highly involved in complex Ph translocations have been relatively mapped. These early results argue against a precise site in 11q13 with which M-Bcr preferentially recombines and favour instead a larger recombination-prone domain. Both of the 11q13 breakpoint regions show Alu repeat elements in close proximity to the site of recombination.

Base Sequence↗

PubMed2002

Galectin-1 is a stromal cell ligand of the pre-B cell receptor (BCR) implicated in synapse formation between pre-B and stromal cells and in pre-BCR triggering.

Although preB cell-receptor (pre-BCR) formation and cell-surface expression is essential for B cell development, pre-BCR generation of signal transduction remains elusive. Here, we report that recombinant pre-BCRs and the surrogate light chain bind specifically to the bone marrow stromal cell galectin-1 (GAL1), an S-type lectin. The surrogate light chain/GAL1 association is a direct protein-protein interaction (K(a) = 2 x 10(6) M(-1)), and the NH(2) extra loop of lambda-like is the major binding element. Pre-BCR binding to stromal cells depends upon GAL1 anchoring to glycosylated counter-receptors, and these complexes completely relocalize to form a synapse at the contact zone between preB and stromal cells. This immune developmental synapse is accompanied by the initiation of intracellular tyrosine kinase activity and signal transduction from the pre-BCR.

Animals↗

PubMed1998

Syk tyrosine kinase and B cell antigen receptor (BCR) immunoglobulin-alpha subunit determine BCR-mediated major histocompatibility complex class II-restricted antigen presentation.

Stimulation of CD4(+) helper T lymphocytes by antigen-presenting cells requires the degradation of exogenous antigens into antigenic peptides which associate with major histocompatibility complex (MHC) class II molecules in endosomal or lysosomal compartments. B lymphocytes mediate efficient antigen presentation first by capturing soluble antigens through clonally distributed antigen receptors (BCRs), composed of membrane immunoglobulin (Ig) associated with Ig-alpha/Ig-beta heterodimers which, second, target antigens to MHC class II-containing compartments. We report that antigen internalization and antigen targeting through the BCR or its Ig-alpha-associated subunit to newly synthesized class II lead to the presentation of a large spectrum of T cell epitopes, including some cryptic T cell epitopes. To further characterize the intracellular mechanisms of BCR-mediated antigen presentation, we used two complementary experimental approaches: mutational analysis of the Ig-alpha cytoplasmic tail, and overexpression in B cells of dominant negative syk mutants. Thus, we found that the syk tyrosine kinase, an effector of the BCR signal transduction pathway, is involved in the presentation of peptide- MHC class II complexes through antigen targeting by BCR subunits.

Animals↗

PubMed2003

Preparation and characterization of reference materials for human pancreatic lipase: BCR 693 (from human pancreatic juice) and BCR 694 (recombinant).

There is a lack of certified reference material (CRM) for lipase catalytic activity. Consequently between-method comparability is very poor. The aim of this study was to produce two lipase CRMs, one from human pancreatic juice (BCR 693), and another using recombinant technologies (BCR 694). Lipase was purified from pancreatic juice, using column chromatography and isoelectric focusing. Recombinant lipase was produced with a transfected cell line and purified with column chromatography. Adding buffered bovine serum albumin and subsequent freeze-drying were used to stabilize both materials. A standardized titrimetric method was employed to compare their catalytic properties to those of two plasma pools of patients suffering from acute pancreatitis. About 5 kU (titrimetry, 37 degrees C) of each material were obtained. They were lyophilized without apparent modifications of their catalytic properties, which stayed identical to those exhibited by the enzyme present in patient's pools. Stability of both materials was estimated at several years when stored in a dry form at -20 degrees C. Both materials appear to have similar catalytic properties and stability and were found commutable as regards a reference method and a routine measurement procedure. An international certification campaign will be carried out to assign values to BCR 693 and BCR 694.

Animals↗

PubMed2005

B cell receptor (BCR) cross-talk: IL-4 creates an alternate pathway for BCR-induced ERK activation that is phosphatidylinositol 3-kinase independent.

IL-4 has pleiotropic effects on B cells. These effects include alteration of subsequent BCR-triggered responses. To identify a molecular basis for this receptor cross-talk, we examined ERK activation and NF-kappaB induction. We found that treatment with IL-4, but not other cytokines, affected subsequent BCR signaling by creating a new pathway in which the need for PI3K in ERK activation was eliminated. In contrast, the need for PI3K in NF-kappaB induction was not altered. The new pathway for ERK required time to develop, depended on STAT6, and was blocked by inhibition of macromolecular synthesis. As in the classical pathway, BCR-induced ERK activation in the new, PI3K-independent pathway required MEK and was reflected in c-Raf. Thus, IL-4 promotes an alternate pathway through which BCR is coupled to Raf/MEK/ERK that may function to heighten the responsiveness of B cells during times of immunological stress.

Animals↗

PubMed2004

Elevated expression of a subset of interferon inducible genes in primary bone marrow cells expressing p185 Bcr-Abl versus p210 Bcr-Abl by DNA microarray analysis.

p185 Bcr-Abl has a more aggressive biological/clinical leukemia phenotype than p210 Bcr-Abl. In this study, we examined differential gene expression using microarrays to determine if upregulation or downregulation of specific genes may explain the distinct phenotypes produced by the two Bcr-Abl forms. RNA was collected from mouse bone marrow mononuclear cells expressing equivalent levels of p185 or p210, and the RNAs were subjected to microarray analysis. Significant differences in gene expression were observed on hierarchical clustering. A group of interferon-gamma-inducible genes, including those encoding a family of 47 kDa GTPases, were significantly increased in p185 versus p210. This family of GTPases has previously been implicated in interferon-gamma-induced resistance against intracellular pathogens, however their exact cellular functions are unknown. Our data suggest that their increased expression may contribute to the biological/clinical phenotype associated with p185.

Animals↗

PubMed1999

Clonally unrelated BCR-ABL-negative acute myeloblastic leukemia masquerading as blast crisis after busulphan and interferon therapy for BCR-ABL-positive chronic myeloid leukemia.

We report a patient with Philadelphia (Ph)-positive, BCR-ABL rearrangement positive, chronic myeloid leukemia (CML) with a prolonged chronic phase of 24 years who was first prescribed alpha-2 interferon 22 years after initial diagnosis. This therapy was tolerated poorly on account of thrombocytopenia, but an eventual major cytogenetic response was followed soon afterwards by transformation to terminal acute myeloid leukemia (AML). Cytogenetic studies indicated that the transformed myeloblasts were karyotypically normal and Ph negative. Although polymerase chain reaction (PCR) analysis of total leukemic mRNA remained BCR-ABL positive, other molecular studies, including Southern blotting and fluorescent in situ hybridization (FISH) analyses, showed that myeloblasts were BCR-ABL rearrangement negative. PCR-based clonality studies using an X-chromosome-linked restriction fragment polymorphism within the phosphoglycerate kinase gene (PGK1) further showed that the Ph-negative blast cells had a different clonal origin from the Ph-positive clone of chronic phase. We suggest that cases of underlying Ph-negative leukemic transformation in Ph-positive CML warrant further study and should be considered for trial of intensive remission induction therapy as appropriate for acute leukemia.

Acute Disease↗

PubMed2005

E6a2 BCR-ABL fusion with BCR exon 5-deleted transcript in a Philadelphia positive CML responsive to Imatinib.

Chronic myeloid leukemia (CML) is characterized in 90% of patients by the presence of the reciprocal translocation t(9;22)(q34;q11) leading to the fusion of the BCR and ABL genes. Most patients with Philadelphia chromosome positive CML express either the e13a2 (b2a2) or e14a2 (b3a2) MBCR-ABL mRNA. Some variant cases have been reported expressing the fusion e1a2 (mBCR-ABL) or e19a2 (microBCR-ABL). Very rare atypical transcripts such as e13a3, e14a3 or e6a2 have been described. We report here a sixth case of a Ph positive patient with an e6a2 BCR-ABL fusion transcript and describe for the first time a chimeric molecule alternatively spliced for exon 5 of the BCR gene.

Aged↗

PubMed1996

Recognition of BCR-ABL positive leukemic blasts by human CD4+ T cells elicited by primary in vitro immunization with a BCR-ABL breakpoint peptide.

In chronic myeloid leukemia (CML) the classical 9;22 translocation results in a BCR-ABL fusion gene, which encodes chimeric BCR-ABL fusion 210 kD oncoproteins (p210BCR-ABL). The two main p210BCR-ABL fusion variants in CML, b2a2 and b3a2 are examples of well characterized antigens expressed by malignant cells. The possibility of an immunotherapeutic approach involving the fusion part of p210BCR-ABL in CML has previously been illustrated by observed peptide binding to major histocompatibility complex (MHC) class I alleles and by demonstrating the immunogenicity of p210BCR-ABL breakpoint peptides. In this report we show that in vitro immunization of human T cells with a 17 amino acid (aa) peptide representing the p210BCR-ABL fusion region resulted in peptide specific CD4+ T-cell lines designated P4, P6, and P7. HLA DR4 (DRB1*0401) restricted T-cell line P4 and several subsequently derived clones recognized HLA-DRB1*0401 and p210b3a2-mRNA expressing blasts from an allogeneic patient with CML in blast crisis. Recognition appeared DR expression-dependent. No responses were observed with DR4 positive p210BCR-ABL negative cells or with p210b3a2 leukemic cells with absent or insufficient expression of DR4. These observations indicate that oncoprotein p210b3a2 can be degraded and processed for presentation by MHC class II molecules at the surface of leukemic cells. The BCR-ABL fusion region is in all likelihood presented as peptides by HLA DR and thus capable to act as a distinctive tumor antigen to peptide specific CD4+ T cells.

Amino Acid Sequence↗

PubMed2001

Fusion of the BCR and the fibroblast growth factor receptor-1 (FGFR1) genes as a result of t(8;22)(p11;q11) in a myeloproliferative disorder: the first fusion gene involving BCR but not ABL.

Constitutive activation of tyrosine kinases as a consequence of chromosomal translocations, forming fusion genes, plays an important role in the development of hematologic malignancies, in particular, myeloproliferative syndromes (MPSs). In this respect, the t(9;22)(q34;q11) that results in the BCR/ABL fusion gene in chronic myeloid leukemia is one of the best-studied examples. The fibroblast growth factor receptor 1 (FGFR1) gene at 8p11 encodes a transmembrane receptor tyrosine kinase and is similarly activated by chromosomal translocations, in which three alternative genes-ZNF198 at 13q12, CEP110 at 9q34, and FOP at 6q27-become fused to the tyrosine kinase domain of FGFR1. These 8p11-translocations are associated with characteristic morphologic and clinical features, referred to as "8p11 MPS." In this study, we report the isolation and characterization of a novel fusion gene in a hematologic malignancy with a t(8;22)(p11;q11) and features suggestive of 8p11 MPS. We show that the breakpoints in the t(8;22) occur within introns 4 and 8 of the BCR and FGFR1 genes, respectively. On the mRNA level, the t(8;22) results in the fusion of BCR exons 1-4 in-frame with the tyrosine kinase domain of FGFR1 as well as in the expression of a reciprocal FGFR1/BCR chimeric transcript. By analogy with data obtained from previously characterized fusion genes involving FGFR1 and BCR/ABL, it is likely that the oligomerization domain contributed by BCR is critical and that its dimerizing properties lead to aberrant FGFR1 signaling and neoplastic transformation.

Aged↗

PubMed2004

Cotreatment with suberanoylanilide hydroxamic acid and 17-allylamino 17-demethoxygeldanamycin synergistically induces apoptosis in Bcr-Abl+ Cells sensitive and resistant to STI571 (imatinib mesylate) in association with down-regulation of Bcr-Abl, abrogation of signal transducer and activator of transcription 5 activity, and Bax conformational change.

Interactions between the histone deacetylase (HDAC) inhibitors suberanoylanilide hydroxamic acid (SAHA) and sodium butyrate (SB) and the heat shock protein (Hsp) 90 antagonist 17-allylamino 17-demethoxygeldanamycin (17-AAG) have been examined in Bcr-Abl(+) human leukemia cells (K562 and LAMA84), including those sensitive and resistant to STI571 (imatinib mesylate). Cotreatment with 17-AAG and SAHA or SB synergistically induced mitochondrial dysfunction (cytochrome c and apoptosis-inducing factor release), caspase-3 and -8 activation, apoptosis, and growth inhibition. Similar effects were observed in LAMA84 cells and K562 cells resistant to STI571, as well as in CD34(+) cells isolated from the bone marrows of three patients with chronic myelogenous leukemia. These events were associated with increased binding of Bcr-Abl, Raf-1, and Akt to Hsp70, and inactivation of extracellular signal-regulated kinase 1/2 and Akt. In addition, 17-AAG/SAHA abrogated the DNA binding and the transcriptional activities of signal transducer and activator of transcription (STAT) 5 in K562 cells, including those ectopically expressing a constitutively active STAT5A construct. Cotreatment with 17-AAG and SAHA also induced down-regulation of Mcl-1, Bcl-xL, and B-Raf; up-regulation of Bak; cleavage of 14-3-3 proteins; and a profound conformational change in Bax accompanied by translocation to the membrane fraction. Moreover, ectopic expression of Bcl-2 attenuated cell death induced by this regimen, implicating mitochondrial injury in the lethality observed. Together, these findings raise the possibility that combining HDAC inhibitors with the Hsp90 antagonist 17-AAG may represent a novel strategy against Bcr-Abl(+) leukemias, including those resistant to STI571.

Apoptosis↗

PubMed2006

Association of the pre-B cell receptor (BCR) expression level with the quality of pre-BII cell differentiation reveals hierarchical pre-BCR function.

The expression of a pre-B cell receptor (pre-BCR) is required for allelic exclusion and pre-BII cell differentiation. V(H)12 microH chains are unusual in that they form pre-BCRs and mediate allelic exclusion, but most cannot drive pre-BII cell differentiation. To explain this paradox, we examined pre-BCR functions and pre-BII cell differentiation in mice expressing microH chain transgenes encoding a B cell-permissible V(H)12 microH chain (designated 10/G4(6-1)), and a non-permissible V(H)12 microH chain (designated 8/G0). Compared with 10/G4 pre-BCRs, 8/G0 pre-BCRs are expressed at low levels on the cell surface. 8/G0 pre-BCRs mediate allelic exclusion, but 8/G0 pre-BII cells are defective in proliferation and expression of survival factors Bcl-2, Bcl-X(L) and hemokinin 1 (HK1). Increasing 8/G0 microH chain production restores HK1 transcription and improves proliferation of pre-BII cells as well as later stage B cell development. These data reveal a hierarchy of pre-BCR function that determines the development and plasticity of early B cells.

Animals↗

PubMed2004

Determination of lipase catalytic activity in two reference materials: BCR 693 and BCR 694 by titrimetry at constant pH.

Because routine assays for pancreatic lipase catalytic activity are not yet standardized, between-method comparability is very poor. This is mainly due to the lack of reference materials (RMs). The aim of this study was to assign values of catalytic concentration to two human pancreatic lipase RMs, one prepared from human pancreatic juice (BCR 693), the other obtained by recombinant technology (BCR 694). Lipase catalytic activity was assayed in five experienced laboratories, using aliquots from the same lot of triolein emulsion and a standardized titrimetric procedure, optimized with regard to substrate, cofactors and pH. The accepted sets of data (n = 4) gave a mean +/- the corresponding uncertainty expressed as the 0.95 confidence interval of 1732 +/- 72 U/l and 1043 +/- 60 U/l for BCR 693 and 694, respectively. Transferability of the whole operating procedure proved to be quite satisfactory. The authors conclude that both RMs can be used to verify the correct implementation of the standardized measurement procedure and to assign values to secondary lipase materials (commercial calibrators, control products) which, in turn, ensures traceability to the standardized procedure in this study, and contributes to the harmonization of laboratory results according to the Directive for in vitro Diagnostic Medical Devices.

Animals↗

PubMed2026

Genetic Profile, Treatment Response, and Outcomes of BCR::ABL1-Positive Mixed-Phenotype Acute Leukemia: A Study From the BCR::ABL1 Pathology Group.

Mixed-phenotype acute leukemia (MPAL) with BCR::ABL1 fusion is rare, and its clinicopathological features, genetic landscape, therapeutic response, and patient outcomes remain incompletely defined, as does its relationship to blast-phase chronic myeloid leukemia. In this multicenter study of 44 patients, 86.4% had B/myeloid MPAL, 72.7% showed lymphoid predominance, 40.9% had complex karyotypes, and 68.3% harbored somatic mutations, most commonly RUNX1 mutations (46.3%). RUNX1 mutations frequently co-occurred with acute myeloid leukemia (AML)-associated alterations, whereas DNMT3A, TET2, and BCORL1 mutations were restricted to RUNX1-mutated cases. In contrast, acute lymphoblastic leukemia (ALL)-associated alterations (IKZF1 mutation/deletion and ETV6 mutations) were confined to RUNX1-wild-type patients. TP53 and signaling pathway mutations (NRAS, KRAS, PTPN11, and FLT3) were not detected. Forty-two patients received induction chemotherapy and/or immunotherapy combined with tyrosine kinase inhibitors: 74.2% of lymphoid-predominant patients and 63.6% of myeloid-predominant patients received ALL- and AML-type therapies, respectively. Ten patients relapsed, and 2 had primary refractory disease; some exhibited a dynamic shift in predominant lineage immunophenotype, chromosomal alterations, and somatic mutations at the relapse or refractory stage. The overall remission rate was 86.8%, with no significant differences across ALL-, AML-, or hybrid-type regimens. After a median follow-up of 24.2 months, the median overall survival was 52.5 months. Complex karyotype was associated with inferior overall survival compared with cases lacking additional chromosomal alterations (P = .02), whereas RUNX1 mutations were not. No significant differences in genetic profiles, treatment response, or outcomes were observed between patients with and without chronic myeloid leukemia-like features. This study provides a comprehensive genomic and clinical characterization of BCR::ABL1-positive MPAL, supporting improved risk stratification and future therapeutic strategies.

Adolescent↗

PubMed1991

Missing Y chromosome in Ph1-negative chronic myeloid leukemia with bcr rearrangement. Evidence for a bcr-abl recombination on chromosome 22 by in situ hybridization.

In a case of Philadelphia chromosome (Ph1)-negative chronic myeloid leukemia (CML) without the Y chromosome, we investigated the differences, at the molecular level, from Ph1-positive CML. Using Southern blot analysis and in situ hybridization studies, we could demonstrate a rearrangement within the breakpoint cluster region (bcr), and the location of a bcr-abl fusion gene on chromosome 22. To our knowledge, this is the first case of Ph1-negative CML with a loss of the Y chromosome in which the molecular abnormalities are shown to be identical with those in Ph1-positive CML.

Chromosome Aberrations↗

PubMed2005

Use of polyclonal rabbit antibodies for detection of the bcr-abl fusion zone in cells transfected with experimental bcr-abl DNA vaccines.

Rabbits were immunized with peptides covering the fusion zone of the chimeric bcr-abl protein in order to prepare antibodies capable of detecting the expression of a selected portion of this fusion zone, by a variety of experimental genetic vaccines. Three peptides of different size covering the b3a2 fusion zone, either unmodified or modified by the omission of alanine at the N-terminal of the a2 section of the fusion zone, and one peptide covering the unmodified b2a2 fusion zone were used. All were capable of eliciting antibodies reactive with the respective immunizing peptides. Their cross-reactivities, especially the results of cross-absorption experiments, strongly suggested that the serum of the rabbit immunized with an octadekapeptide mimicking the b3a2 fusion zone contained antibodies against a novel antigenic determinant created by the chimeric protein, and also against an epitope present in the adjacent a2 section but no antibody reactive with the adjacent b3 region. In Western blotting, these antibodies were capable of detecting the p210bcr-abl or a portion of it (a 25 amino acid-long sequence covering the b3a2 fusion zone) in lysates of 293T cells transfected with plasmids that carried either the full cDNA of the bcr-abl gene or a fragment thereof fused with either the HSP70 gene or certain other genes.

Animals↗