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At least 1,081 records · Page 60Linked to original sources
PubMed1996

Aberrant B cell development and immune response in mice with a compromised BCR complex.

The immunoglobulin alpha (Ig-alpha)-Ig-beta heterodimer is the signaling component of the antigen receptor complex on B cells (BCR) and B cell progenitors (pre-BCR). A mouse mutant that lacks most of the Ig-alpha cytoplasmic tail exhibits only a small impairment in early B cell development but a severe block in the generation of the peripheral B cell pool, revealing a checkpoint in B cell maturation that ensures the expression of a functional BCR on mature B cells. B cells that do develop demonstrate a differential dependence on Ig-alpha signaling in antibody responses such that a signaling-competent Ig-alpha appears to be critical for the response to T-independent, but not T-dependent, antigens.

Animals↗
PubMed1989

A bcr-v-abl oncogene induces lymphomas in transgenic mice.

In chronic myeloid leukemia and some cases of acute lymphoblastic leukemia, a 9;22 chromosome translocation has fused most of the c-abl oncogene to a gene designated bcr. To explore in vivo the biological effects of the chimeric gene, we introduced a facsimile of the translocation product, a bcr-v-abl gene, into the mouse germ line under the control of the immunoglobulin heavy-chain enhancer or a retroviral long terminal repeat. Some transgenic mice bearing either construct developed clonal lymphoid tumors. T lymphomas predominated, but some pre-B lymphomas developed. The transgenes were expressed in the tumors but not detectably in the lymphoid tissues of nontumorous transgenic animals, implying that transcription is activated by a low-frequency somatic event. These results demonstrate that bcr-v-abl is tumorigenic in vivo and provide a new animal model for lymphomagenesis.

Animals↗
PubMed2005

NS-187, a potent and selective dual Bcr-Abl/Lyn tyrosine kinase inhibitor, is a novel agent for imatinib-resistant leukemia.

Although the Abelson (Abl) tyrosine kinase inhibitor imatinib mesylate has improved the treatment of breakpoint cluster region-Abl (Bcr-Abl)-positive leukemia, resistance is often reported in patients with advanced-stage disease. Although several Src inhibitors are more effective than imatinib and simultaneously inhibit Lyn, whose overexpression is associated with imatinib resistance, these inhibitors are less specific than imatinib. We have identified a specific dual Abl-Lyn inhibitor, NS-187 (elsewhere described as CNS-9), which is 25 to 55 times more potent than imatinib in vitro. NS-187 is also at least 10 times as effective as imatinib in suppressing the growth of Bcr-Abl-bearing tumors and markedly extends the survival of mice bearing such tumors. The inhibitory effect of NS-187 extends to 12 of 13 Bcr-Abl proteins with mutations in their kinase domain but not to T315I. NS-187 also inhibits Lyn without affecting the phosphorylation of Src, Blk, or Yes. These results suggest that NS-187 may be a potentially valuable novel agent to combat imatinib-resistant Philadelphia-positive (Ph+) leukemia.

Animals↗
PubMed2006

Combined deficiencies in Bruton tyrosine kinase and phospholipase Cgamma2 arrest B-cell development at a pre-BCR+ stage.

Bruton tyrosine kinase (Btk) and phospholipase Cgamma2 (PLCgamma2) are 2 key molecules involved in B-cell receptor (BCR) signaling. Biochemical studies have placed them in a linear signaling pathway, with Btk acting upstream of PLCgamma2. Consistent with this, mice lacking either molecule display a leaky but similar block in B-cell development. Here, we generated Btk(-/-) PLCgamma2(-/-) mice and showed that combined deficiencies in Btk and PLCgamma2 severely arrested B lymphopoiesis at the large pre-B-cell stage. In contrast to either single mutant, Btk(-/-) PLCgamma2(-/-) pre-B cells expressed high levels of pre-BCR on their cell surfaces and exhibited reduced immunoglobulin light chain gene rearrangements. Pre-BCR-induced calcium signaling was also drastically compromised in Btk(-/-) PLCgamma2(-/-) pre-B cells compared with wild-type and single-mutant cells. Interestingly, immunoglobulin heavy chain allelic exclusion remained intact in the absence of Btk and PLCgamma2. Overall, our results suggest that Btk and PLCgamma2 have combinatorial roles in regulating pre-B cell differentiation.

Agammaglobulinaemia Tyrosine Kinase↗
PubMed2001

Certification of the mass concentration of creatine kinase isoenzyme 2 (CK-MB) in the reference material BCR 608.

We describe the certification of a mass concentration value in the already prepared creatine kinase-2 reference material (BCR 608). Creatine kinase-2 was purified from human heart. The purified enzyme was diluted in order to measure its protein concentration by the Doetsch method. A protein concentration value of 124.30+/-13.17 mg/l was assigned to the stock solution of purified creatine kinase-2. This stock solution was diluted in 25 mmol/l piperazine-N,N'-bis[2-ethanesulfonic acid] (PIPES) pH 7.2, containing 2 mmol/l ADP, 5 mmol/l 2-mercaptoethanol, 154 mmol/l sodium chloride and 50 g/l human albumin to obtain a stable liquid standard of known creatine kinase-2 mass concentration (80.36 microg/l). This standard was then used to recalculate the creatine kinase-2 mass concentration measured in the BCR 608 material by immunoassay. The mass concentration of creatine kinase-2 in samples of reconstituted BCR 608 was certified to be 93.30+/-9.65 microg/l.

Calibration↗
PubMed1998

Abnormal stress response and increased fighting behavior in mice lacking the bcr gene product.

The in vivo function of proteins which regulate activity of the GTPase Rac is largely unknown. Here we establish that mice lacking bcr, a known GTPase activating protein for Rac, exhibit a defect in the regulation of both hormonal and behavioral stress responses. Bcr null mutants demonstrate prolonged elevation of plasma glucocorticoids and increased fighting in males in response to physiological and social stress, respectively. Combined biochemical and behavioral data indicate that bcr is involved in mediating the cellular effects of glucocorticoids, specifically down-regulation of the stress-activated hippocampal hypothalamic-pituitary-adrenal axis.

Aggression↗
PubMed2000

[Constructing a Competitor of BCR-ABL cDNA by PCR Site-Directed Mutagenesis]

A competitive mimic of the cDNA of the BCR-ABL fusion gene was constructed, and its feasibility was testified by capillary electropheresis (CE). The 4 bp-shorter mimic was obtained by PCR amplification using a newly synthesized downstream primer analogous to the former one. Mimics of both types of BCR-ABL cDNA were achieved and the validity was verified with restriction endonuclease. And the products of the coamplification PCR could be easily separated by capillary electrophorisis. The mimic can be used to quantitative detection of BCR-ABL gene through competitive RT-PCR in chronic myeloid leukemia.

Journal Article↗
PubMed2003

[The reverse effect on drug-resistance against tyrosine kinase inhibitor STI571 in mdr1 and bcr-abl positive leukemic cells].

To explore the possibility of leukemia cell line of both bcr-abl and mdr-1 positive were cross-resistant to tyrosine kinase inhibitor STI571 and its reversal way, the inhibitory effect of STI571 on K562-n/VCR cells was detected with MTT method and reverse effects of CsA, TAM, IFN-alpha and CsA cominated with IFN-alpha were observed. The results showed that K562-n/VCR cell line expressing bcr-abl and mdr1 positive was resistant to STI571, and could be reversed by 5.18, 1.82 and 1.67-fold respectively, when treated with CsA, TAM, and IFN-alpha. It could be reversed by 34.87-fold with combination of half-dose CsA and IFN-alpha. In conclusion, amplification of mdr1 gene may contribute to drug-resistance of bcr-abl positive leukemic cells against STI571. The reversal agents, CsA, TAM and IFN-alpha show obviously reverse effects on drug-resistance. The combination of half-dose of both CsA and IFN-alpha display stronger effect than the full dose of either.

Antineoplastic Agents↗
PubMed2004

[Synergistic inhibitory effect of STI571 in combination with arsenic trioxide on a multidrug-resistant leukemia cell line expressing bcr-abl].

OBJECTIVE: To study the synergistic effect of STI571, an inhibitor of tyrosine kinase in combination with arsenic trioxide (As(2)O(3)) on a multidrug-resistant leukemia cell line expressing bcr-abl. METHODS: The cytotoxic effect of STI571 alone or in combination with different concentrations of As(2)O(3) on both bcr-abl and mdr1 positive leukemia cell line K562-n/VCR was detected by MTT method. RESULTS: The cytotoxic effect of STI571 (1 micromol/L) combined with As(2)O(3) at concentrations 10(-5), 10(-6), 10(-7), 10(-8) mol/L (IC(50) 0.155 micromol/L) on K562-n/VCR cells was significantly higher than that of As(2)O(3) alone (IC(50) 1.879 micromol/L). The synergistic interaction on K562-n/VCR cells increased the cytotoxic effect by 12.1-fold. CONCLUSION: Combination of STI571 with As(2)O(3) has a synergistic inhibiting effect on leukemia cells expressing bcr-abl and mdr1.

Antineoplastic Agents↗
PubMedDate not supplied

The BCR signalosome: where cell fate is decided.

B cell antigen receptor (BCR) engagement results in the assembly of a multimolecular complex at the cytosolic side of the plasma membrane, known as signalosome. Here we briefly review the current knowledge on the molecules which participate in the BCR signalosome and on the response modulators which control the final signal output by enhancing or dampening BCR signaling.

Adaptor Proteins, Signal Transducing↗
PubMedDate not supplied

Effect of ultrasound agitation on the release of heavy elements in Certified Reference Material of human hair (CRM BCR 397).

An ultrasonic-assisted leaching procedure was developed for the determination of heavy elements (As, Cu, Cd, Pb, and Zn) in Certified Reference Material of human hair (CRM 397) provided from the Community Bureau of Reference (BCR) of the Commission of the European Community. Concentrated nitric acid-30% hydrogen peroxide (2 + 1) was used for the leaching method. The effects of different factors on acid leaching of elements, such as presonication time (without ultrasonic stirring), sonication or exposure time to ultrasound, and temperature of the ultrasonic bath have been investigated. Optimum values of these parameters were selected for the maximum extraction of heavy metals from CRM BCR 397 and human scalp hair samples of normal healthy males. To check the validity of the proposed method, a wet acid digestion method was used to obtain the total elemental concentration in CRM BCR 397 and scalp hair samples. Cu and Zn in leachate and digests were measured by flame atomic absorption spectrometry using a conventional air/acetylene flame, while As, Cd, and Pd were determined by electrothermal atomic absorption spectrometry. Under optimized conditions, the recovery for Zn, Cd, Pd, As, and Cu was 98, 98.5, 97.5, 98.2, and 95%, respectively, of those obtained with the wet acid digestion method.

European Union↗
PubMed2004

Chronic myeloid leukemia with an e13a3 BCR-ABL fusion: benign course responsive to imatinib with an RT-PCR advisory.

A case of a patient with chronic myeloid leukemia whose cells expressed an e13a3 (b2a3) variant BCR-ABL p210 mRNA is presented. The variant splice was detected by a qualitative reverse transcriptase polymerase chain reaction using primers complementary to BCR exon 13 (b2) and ABL exon 3 (a3). The patient responded well to imatinib and achieved a complete cytogenetic response.

Adult↗
PubMed2005

Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center: a 4.5-year follow-up.

BACKGROUND: The advent of imatinib has considerably changed the treatment of chronic myeloid leukemia (CML). Early studies demonstrated high rates of hematologic and cytogenetic responses in all phases of the disease after limited observation periods. METHODS: The authors evaluated long-term outcome, rates of response, and resistance in 300 patients with BCR-ABL-positive leukemias (CML in chronic phase after failure to respond to interferon-alpha [CP], n = 139; accelerated phase [AP], n = 80; myeloid blast crisis [BC], n = 76; lymphoid BC and Philadelphia chromosome-positive acute lymphoblastic leukemia, n = 5) who entered clinical trials with imatinib in a single center after an observation time of 4.5 years. RESULTS: In CP, hematologic remission was achieved in 97% and major (MCR) and complete cytogenetic remission (CCR) in 61% and 49% of patients, respectively. The chance to achieve MCR was higher in patients commencing imatinib earlier in the course of CML. In AP, the median survival period after the start of imatinib was 44 months, and MCR and CCR were observed in 31% and 26% of patients, respectively. In myeloid BC, the median survival period after the start of imatinib and after diagnosis of BC was 6 and 9 months, respectively. Hematologic resistance occurred in 25%, 41%, and 92% of patients in CP, AP, and myeloid BC, respectively, and was associated with BCR-ABL mutations in 45% of patients and with clonal evolution in 58% of patients. CONCLUSIONS: The data emphasized the need for a prolonged follow-up of patients treated with imatinib to define the clinical potential of the drug and to establish methods to optimize therapy.

Adolescent↗
PubMed2007

Nuclear positioning of the BACH2 gene in BCR-ABL positive leukemic cells.

BACH2 is a B-cell-specific transcription repressor and is also know as a tumor suppressor in B cell malignancy. Expression of BACH2 is induced in BCR-ABL positive lymphoid cell lines including BV173 by imatinib, a molecular targeting agent for the treatment of chronic myeloid leukemia (CML). Here we show that the activity of the BACH2 gene is related to the nuclear positioning of the gene loci. We examined the spatial association of the BACH2 gene with the centromeric heterochromatin, a transcriptionally repressive subnuclear compartment, by comparing cells with low (BV173 and K562) and high (NAMALWA) levels of BACH2 mRNA. The BACH2 gene was located closer to the centromeric heterochromatin in BV173 and K562 cells as compared to NAMALWA cells. In BV173 cells, the BACH2-centromere distance increased after imatinib treatment to levels similar to those in NAMALWA cells. We also found that diethylmaleate, an oxidative stressor, enhanced the antiproliferative effect of imatinib in only BV173 cells. Since BACH2 induces apoptosis by oxidative stress, these observations suggest that down-regulation of the BACH2 gene through the interaction with centromeric heterochromatin would take part in leukomogenesis of BCR-ABL positive lymphoid leukemia.

Antineoplastic Agents↗
PubMed1990

Molecular and cytogenetic studies of a patient with Philadelphia-negative, BCR-positive chronic myeloid leukemia and t(12;12)(q13;p12).

A patient with Philadelphia (Ph1)-negative, breakpoint cluster region (bcr)-positive chronic myeloid leukemia (CML) is reported. Pulsed-field gel electrophoretic analysis demonstrated the comigration of both ABL and BCR sequences on the same BssHII and SacII fragment. Moreover, in situ hybridization studies demonstrated that ABL sequences had been moved from band 9q34 to 22q11 and that the additional t(12;12)(q13;p12) was not involved in the ABUBCR related translocation. Nevertheless, a possible role of oncogenes or regulatory sequences activated or inhibited by the additional translocation cannot be excluded.

Adult↗
PubMed1992

Ph-positive chronic myeloid leukemia with loss of the segment distal to M-bcr.

We describe a patient with chronic myeloid leukemia (CML) and a 22q- but no 9q+ chromosome. Southern blot analysis showed a BCR rearrangement. The patient soon developed profound and superficial thrombophlebitis in arms and legs and died from pulmonary embolisation 15 days after diagnosis. Five CML cases with a deletion of 22q but no known translocation of 22q11----qter have been described earlier. The present patient is the first such case, however, in whom a BCR rearrangement has been demonstrated.

Blast Crisis↗
PubMed2004

Imatinib mesylate effectively combines with chaperone-rich cell lysate-loaded dendritic cells to treat bcr-abl+ murine leukemia.

Imatinib mesylate has become an effective agent for the treatment of chronic myeloid leukemia (CML). However, the development of drug resistance has led to examination of combination therapies. In this study, we investigated the effects of combining imatinib with immunotherapy against a murine bcr-abl(+) leukemia, 12B1. We have previously shown that multiple chaperone proteins may be enriched into a vaccine form from tumor cell lysates by a free-solution isoelectric focusing method. We refer to these vaccines as chaperone-rich cell lysates (CRCLs) and have found that they are potent immunologic agents against a variety of murine tumors, including 12B1. We now demonstrate that the combination of imatinib with dendritic cells loaded with 12B1-derived CRCL yields high activation of anti-12B1-specific T cells and potent antitumor activity, resulting in tumor-free survival in up to 63% of mice with bcr-abl(+) 12B1 tumors. Our data suggest that immunotherapy can be effectively combined with imatinib for the treatment of CML.

Animals↗
PubMed1995

Sequence specificity on the growth suppression and induction of apoptosis of chronic myeloid leukemia cells by BCR-ABL anti-sense oligodeoxynucleoside phosphorothioates.

Sequence specificity of inhibitory effects of various BCR-ABL anti-sense oligodeoxynucleoside phosphorothioates (AS PS-ODN) on the proliferation of the chronic myeloid-leukemia cell line BV173 was examined. We confirmed that 26, 18, and 16mer B2A2 AS PS-ODN had strong inhibitory effects on the proliferation of BV173 cells with B2A2 mRNA expression, and that B3A2 AS PS-ODN were equally inhibitory when cultures were initiated at lower cell concentrations. However, at higher cell concentrations, the inhibitory effects by B3A2 AS PS-ODN were reduced and B2A2 AS PS-ODNs could suppress the proliferation of BV173 cells with much more relative sequence specificity. The 26mer B2A2 AS PS-ODN induced apoptosis of BV173 cells following reduction of BCR-ABL mRNA expression and p210 protein synthesis. Various sense (S), reverse order, and random sequences had no inhibitory effects except 16mer B2A2 S and B3A2 S that revealed significant suppressive effects. Furthermore, 26mer B3A2 AS also reduced B2A2 mRNA expression and p210 protein synthesis, while 16mer S sequences did not. These results suggest that B2A2 AS may be cross-reactive with B3A2 AS on the growth suppression of CML cells under certain culture conditions, possibly due to their partial hybridization to the ABL portion of the target mRNA, although other non-sequence-specific mechanisms are also possible.

Base Sequence↗