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PubMed2003

Identification of a pre-BCR lacking surrogate light chain.

SLP-65-/- pre-B cells show a high proliferation rate in vitro. We have shown previously that lambda5 expression and consequently a conventional pre-B cell receptor (pre-BCR) are essential for this proliferation. Here, we show that pre-B cells express a novel receptor complex that contains a micro heavy chain (microHC) but lacks any surrogate (SL) or conventional light chain (LC). This SL-deficient pre-BCR (SL-pre-BCR) requires Ig-alpha for expression on the cell surface. Anti-micro treatment of pre-B cells expressing the SL-pre-BCR induces tyrosine phosphorylation of substrate proteins and a strong calcium (Ca2+) release. Further, the expression of the SL-pre-BCR is associated with a high differentiation rate toward kappaLC-positive cells. Given that B cell development is only partially blocked and allelic exclusion is unaffected in SL-deficient mice, we propose that the SL-pre-BCR is involved in these processes and therefore shares important functions with the conventional pre-BCR.

Animals↗
PubMed2003

Convergence of CpG DNA- and BCR-mediated signals at the c-Jun N-terminal kinase and NF-kappaB activation pathways: regulation by mitogen-activated protein kinases.

Depending on the experimental model, unmethylated CpG motifs in bacterial DNA or synthetic oligodeoxynucleotides (CpG DNA) either augment or antagonize BCR-induced signals in B cells. CpG DNA synergizes with BCR-induced proliferation and Ig production of mature B cells, but blocks BCR-mediated apoptosis of immature B cells. Here, we demonstrate using a murine B lymphoma cell line WEHI-231, which is a model for immature B lymphocytes, that CpG DNA augments BCR-mediated signals for the activation of mitogen-activated protein kinase (MAPK) kinase (MKK)3, MKK4 and MKK6, and their subsequent downstream effectors c-Jun N-terminal kinase (JNK) and p38, but does not enhance MEK1/2 or extracellular signal-regulated kinase (ERK) activation. CpG DNA- and BCR-mediated signals also synergize for the activation of transcription factors AP-1, NFAT and NF-kappaB, but not for cAMP-responsive elements binding factor. Synergistic activations of JNK and p38 contribute to the synergistic production of cytokines induced by CpG DNA- and BCR-mediated signals, but have little or no effect on the ability of CpG DNA to protect WEHI-231 cells from anti-IgM-induced growth arrest. In contrast, all three MAPK, JNK, ERK and p38, contribute to the synergistic induction of splenic mature B cell proliferation by CpG DNA and anti-IgM. These results indicate that CpG DNA- and BCR-mediated signals converge at the level of MKK, NF-kappaB and NFAT activation, and that MAPK have differential regulatory roles for CpG DNA-mediated cytokine production versus cell proliferation in splenic mature B cells and WEHI-231 cells.

Animals↗
PubMed1989

ABR, an active BCR-related gene.

The human BCR gene on chromosome 22 is specifically involved in the Philadelphia translocation, t(9;22), a chromosomal rearrangement present in the leukemic cells of patients with chronic myeloid leukemia or acute lymphoblastic leukemia. In most cases, the breakpoints on chromosome 22 are found within a 5.8 kb region of DNA designated the major breakpoint cluster region (Mbcr) of the BCR gene. Hybridization experiments have indicated that the human genome contains BCR gene-related sequences. Here we report the molecular cloning of one of these loci, for which we propose the name ABR. In contrast with the other BCR-related genes studied to date, ABR represents a functionally active gene and contains exons very similar to those found within the Mbcr. Unlike the BCR gene, the ABR gene exhibits great genomic variability caused by two different variable tandem repeat regions located in two introns. All other BCR gene-related sequences isolated so far and the BCR gene itself are located on chromosome 22. In contrast, the ABR gene is located on chromosome 17p.

Amino Acid Sequence↗
PubMed2000

The survival function of the Bcr-Abl oncogene is mediated by Bad-dependent and -independent pathways: roles for phosphatidylinositol 3-kinase and Raf.

The Bcr-Abl tyrosine kinase constitutively activates cytokine signal transduction pathways that stimulate growth and prevent apoptosis in hematopoietic cells. The antiapoptotic action of interleukin-3 (IL-3) has been linked to a signaling pathway which inactivates the proapoptotic protein Bad by phosphorylation through kinases such as Akt and Raf. Here we report also that expression of Bcr-Abl leads to phosphorylation of Bad in hematopoietic cells. Bad phosphorylation induced by Bcr-Abl is kinase dependent, requires phosphatidylinositol 3-kinase (PI3-kinase), and mitochondrial targeting of Raf, and occurs independently of Erk. The ability of Bcr-Abl to confer cytokine-independent survival to hematopoietic cells was compromised by inhibitors of PI3-kinase, as well as by a dominant negative form of Raf targeted to the mitochondria. Furthermore, when the capacity of Bcr-Abl to phosphorylate Bad was completely blocked by dominant negative Raf, a subpopulation of cells remained viable, providing evidence for Bad-independent survival pathways. This alternative survival pathway remained PI3-kinase dependent. Finally, Bcr-Abl, but not IL-3, inhibited the proapoptotic activity of overexpressed Bad. We conclude that the antiapoptotic function of Bcr-Abl is mediated through pathways involving PI3-kinase and Raf and that survival can occur in the absence of Bad phosphorylation.

Apoptosis↗
PubMed2004

[Inhibitory effect of siRNA on bcr-abl gene expression in K562 cell line].

To explore a new way to treat CML, inhibitory effect of small interfering RNA (SiRNA) on bcr-abl fusion gene expression of K562 cell line was studied. SiRNA for bcr-abl gene was designed and transfected into K562 cells, bcr-abl gene expression was tested by RT-PCR. The results showed that bcr-abl gene expression was inhibited by using siRNA in dose-dependent manner and reduced to 19.9% and 26.6% of the control at 24 and 48 hours after transfection with 0.2 micro g siRNA respectively. K562 cells proliferation was suppressed finally, but bcr-abl gene expression restored at 72 hours. In conclusion, anti-bcr-abl siRNA can effectively inhibit bcr-abl gene expression of K562 cell line.

Dose-Response Relationship, Drug↗
PubMed1988

bcr-abl oncogene activation in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Tumor-specific alterations in oncogenes are thought to play a central role in the development of cancer. An example is the consistent fusion of the bcr gene to the c-abl oncogene on the Ph chromosome in CML. The Ph chromosome can also be observed in ALL. About 50% of Ph+ ALL cases, in contrast to CML, do not exhibit chromosomal breakpoints in the major cluster region or mcr (Ph+ mcr- ALL). These cases may have a novel bcr-abl fusion gene instead. We tested this hypothesis in eight Ph+ mcr- ALL patients by amplifying the putative hybrid part of the bcr-abl cDNA, using the polymerase chain reaction method. All cases examined showed the same joining of the first exon of the bcr gene to the c-abl oncogene. Thus, the novel bcr-abl fusion in Ph+ mcr- ALL is the result of a molecularly distinct Ph chromosome. This allows the definition of Ph+ leukemias by their respective bcr-abl oncogene activation. Moreover, the cDNA amplification method we use is a clinically useful tool to screen for bcr-abl oncogene activations in leukemia patients.

DNA, Neoplasm↗
PubMed1987

Heterogeneity in expression of the bcr-abl fusion transcript in CML blast crisis.

The 9;22 Philadelphia chromosome translocation in chronic myelogenous leukemia (CML) generates a bcr-abl fusion gene which codes for an aberrant 8-kb bcr-abl hybrid message. CML blast crisis cell lines display enhanced in vitro expression of this aberrant bcr-abl transcript when compared with fresh CML chronic phase cells. We directly compared in fresh patient samples the level of expression of the bcr-abl transcript in CML blast crisis versus chronic phase cells. All chronic phase patients displayed relatively low amounts of this aberrant transcript, while four of 10 blast crisis patients expressed this transcript at significantly higher levels. The remaining six blast crisis samples exhibited low levels of the aberrant transcript comparable to chronic phase cells. The two patients displaying the highest levels of the bcr-abl transcript did not harbor amplified copies of the bcr-abl fusion gene. This heterogeneity in the level of expression of the bcr-abl transcript in CML blast crisis indicates that enhanced expression of this aberrant transcript is not an absolutely necessary condition for blast transformation.

Adult↗
PubMed1986

bcr rearrangement and translocation of the c-abl oncogene in Philadelphia positive acute lymphoblastic leukemia.

The Philadelphia (Ph1) chromosome, the cytogenetic hallmark of chronic myeloid leukemia (CML), has also been detected in a significant number of acute lymphoblastic leukemias (ALL). Using in situ hybridization, we demonstrate that in accordance with observations in CML the Ph1 chromosome in ALL patients is the result of a consistent translocation of the c-abl oncogene to the Ph1 chromosome. Southern blot analysis using bcr probes, however, suggests that Ph1-positive ALL includes heterogeneous leukemic subtypes: six ALL patients showed bcr rearrangements as observed in CML; in three other patients recombination involving 5' bcr sequences could be demonstrated, but the corresponding translocated 3' bcr sequences were not detectable. A third group of five patients did not show any bcr rearrangements at all. Northern blot analysis using RNA from three Ph1-positive ALL patients revealed that in the leukemic cells of two patients larger c-abl mRNA transcripts were present, as in CML. In the RNA of one patient without a detectable bcr rearrangement, only the normal c-abl mRNA transcripts are present. The observed heterogeneity in bcr rearrangements of this group of Ph1-positive ALL patients is in contrast with the consistent results obtained in more than 50 Ph1-positive CML patients investigated in chronic and acute states.

Chromosome Deletion↗
PubMed1997

Peptides derived from the whole sequence of BCR-ABL bind to several class I molecules allowing specific induction of human cytotoxic T lymphocytes.

Chronic myeloid leukemia (CML) is characterized cytogenetically by a t(9;22) translocation which generates a hybrid bcr-abl gene, encoding a p210(bcr-abl) fusion protein. The induction in vitro of leukemia-specific T cells reactive with p210(bcr-abl) is a strategy developed for an immunological therapeutic approach in CML. Peptides from the junction region of this chimeric protein have been considered as potential targets for a cytotoxic response against leukemic cells. However, only a few peptides encompassing the two p210(bcr-abl) breakpoints have been shown to bind to the most common HLA class I molecules, which limits the number of patients who could benefit from this approach. We assume that the presence of chimeric BCR-ABL protein in leukemic cells may affect processing and delivery of peptides, possibly giving rise to new epitopes at the cell surface. We selected 162 peptides from the whole sequence of this protein, including 14 peptides of the b2a2 and b3a2 junctions, which had an anchor motif for a common HLA class I molecule. We tested their ability to bind to eight HLA class I molecules (HLA-A1, -A2, -A3, -A11, -B7, -B8, -B27, -B44). We identified 48 peptides from outside the junction region, with intermediate or strong binding capacities to these HLA class I molecules contrasting with only six junction peptides with a moderate binding capacity to HLA-A3/A11, -B8, or -B44 molecules. Moreover, cytotoxic T lymphocyte lines specific for various peptides outside the junction were generated from peripheral blood mononuclear cells of HLA-A2 or -B7 healthy donors and from one CML patient. These results contribute to evaluation of immunity to the BCR-ABL chimeric protein. Further studies are required to investigate whether such epitopes are correctly processed and presented by leukemic cells.

Amino Acid Sequence↗
PubMed2005

A BCR-JAK2 fusion gene as the result of a t(9;22)(p24;q11.2) translocation in a patient with a clinically typical chronic myeloid leukemia.

Chronic myeloid leukemia (CML) is characterized by the presence of a t(9;22)(q34;q11.2), which leads to the well-known BCR-ABL1 fusion protein. We describe a patient who was diagnosed clinically with a typical CML but on cytogenetic analysis was found to have a t(9;22)(p24;q11.2). Chromosomal fluorescence in situ hybridization showed that the BCR gene locus spanned the breakpoint at band 22q11.2 but that the ABL1 gene was not rearranged. By means of a candidate gene approach, the JAK2 gene, at 9p24, was identified as the fusion partner of BCR in this case. The BCR-JAK2 fusion protein contains the coiled-coil dimerization domain of BCR and the protein tyrosine kinase domain (JH1) of JAK2. The patient's disease did not respond to Imatinib, and this unresponsiveness was most likely a result of the BCR-JAK2 fusion protein.

Antineoplastic Agents↗
PubMed1995

Sequence and analysis of the human ABL gene, the BCR gene, and regions involved in the Philadelphia chromosomal translocation.

The complete human BCR gene (152-141 nt) on chromosome 22 and greater than 80% of the human ABL gene (179-512 nt) on chromosome 9 have been sequenced from mapped cosmid and plasmid clones via a shotgun strategy. Because these two chromosomes are translocated with breakpoints within the BCR and ABL genes in Philadelphia chromosome-positive leukemias, knowledge of these sequences also might provide insight into the validity of various theories of chromosomal rearrangements. Comparison of these genes with their cDNA sequences reveal the positions of 23 BCR exons and putative alternative BCR first and second exons, as well as the common ABL exons 2-11, respectively. Additionally, these regions include the alternative ABL first exons 1b and 1a, a new gene 5' to the first ABL exon, and an open reading frame with homology to an EST within the BCR fourth intron. Further analysis reveals an Alu homology of 38.83 and 39.35% for the BCR and ABL genes, respectively, with other repeat elements present to a lesser extent. Four new Philadelphia chromosome translocation breakpoints from chronic myelogenous leukemia patients also were sequenced, and the positions of these and several other previously sequenced breakpoints now have been mapped precisely, although no consistent breakpoint features immediately were apparent. Comparative analysis of genomic sequences encompassing the murine homologues to the human ABL exons 1b and 1a, as well as regions encompassing the ABL exons 2 and 3, reveals that although there is a high degree of homology in their corresponding exons and promoter regions, these two vertebrate species show a striking lack of homology outside these regions.

Animals↗
PubMed1994

Persistence of bcr-abl mRNA-expressing cells in long-term cultures established from chronic myeloid leukemic bone marrow or blood.

Long-term cultures (LTC) established from chronic myeloid leukemic (CML) bone marrow or blood contain bcr-abl mRNA-expressing cells, as demonstrated by the polymerase chain reaction (PCR). Bcr-abl sequences were detectable in cultures from all of nine patients investigated. In LTC from two patients, in which a cytogenetic conversion from Ph+ to Ph- was noted at day 20 and 40, respectively, the PCR for bcr-abl remained positive, at least up to day 112 and 245, respectively, in vitro. The differences between the results of cytogenetic and PCR analyses was explained by the fact that the metaphases studied were obviously derived from spontaneously EBV-transformed bcr-abl mRNA-negative B cells, which may become the dominating cell type very early in LTC from bone marrow or blood. LTCs cloned for EBV-transformed B cells which no longer harbor admixed macrophages are bcr-abl mRNA negative. In conclusion, bcr-abl mRNA-expressing cells may show long-term persistence in LTC established from CML bone marrow or blood.

Adult↗
PubMed2002

Bcr-Abl is a "molecular switch" for the decision for growth and differentiation in hematopoietic stem cells.

Chronic myeloid leukemia (CML) is a clonal disorder originating in the pluripotent hematopoietic stem cell (HSC), the hallmark of which is the constitutively activated p210-type of Bcr-Abl tyrosine kinase protein. Studies in recent years have helped us to understand the molecular processes involved in the initiation and progression of CML. Although a great amount of knowledge has been accumulated, the effect of Bcr-Abl on the HSC is still unclear. We have developed an in vitro system that mirrors the chronic phase of CML with a combination of in vitro embryonic stem cell differentiation and tetracycline-inducible Bcr-Abl expression. Enforced Bcr-Abl expression was sufficient to increase the number of both multilineage progenitors and myeloid progenitors. The current system is powerful for analyzing the genetic changes in hematopoietic development. This review focuses on how Bcr-Abl affects HSCs and how Bcr-Abl expression alters the properties of HSCs.

Animals↗
PubMed2001

Dendritic-cell-peptide immunization provides immunoprotection against bcr-abl-positive leukemia in mice.

Chronic myelogenous leukemia (CML) is a clonal disorder characterized by proliferation of cells that possess the bcr-abl fusion gene resulting in the production of one of two possible chimeric 210-kDa tyrosine kinase proteins. Since these chimeric proteins are expressed only in leukemic cells they have the potential to serve as tumor-specific antigens for cytotoxic T lymphocytes (CTL). Using the 12B1 murine leukemia cell line, derived by retroviral transformation of BALB/c bone marrow cells with the bcr-abl (b3a2) fusion gene, we have demonstrated that intravenous inoculation of 12B1 cells into BALB/c mice results in a disseminated acute leukemia analogous to human CML in blast crisis. Histological sections of liver and spleen and polymerase chain reaction analysis of peripheral blood, bone marrow, liver, spleen and lymph nodes confirmed the presence of bcr-abl+ leukemia cells in these murine tissues, while Western blot data demonstrated the expression of the fusion protein in 12B1 cells. Immunization of mice with dendritic cells (DC) loaded with the synthetic bcr-abl chimeric nonapeptide, GFKQSSKAL, led to a 150 times higher frequency of bcr-abl-specific CTL precursors in the spleen than in mice immunized with peptide alone. In vitro re-stimulation of DC-peptide-primed splenocytes resulted in substantial secretion of interferon gamma and augmented cytolytic activity against 12B1 targets. Finally, vaccination with peptide-loaded DC significantly prolonged survival of BALB/c mice that were challenged with 12B1 leukemia. The capacity to generate bcr-abl-specific CTL in vivo by DC-based immunization may have clinical implications in the treatment of CML.

Animals↗
PubMed2000

The amount of BCR-ABL fusion transcripts detected by the real-time quantitative polymerase chain reaction method in patients with Philadelphia chromosome positive chronic myeloid leukemia correlates with the disease stage.

The use of the real-time reverse-transcription polymerase-chain reaction (RT-PCR) method to quantify BCR-ABL transcripts before and after allogeneic transplant was prospectively studied in 65 patients with chronic myeloid leukemia (CML). The expression of the BCR-ABL transcript was determined and normalized using the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) housekeeping gene product as an endogenous reference. In the single step real-time PCR assay, tenfold serial dilutions of cDNA of the K5652 cell line remained positive down to 100 pg cDNA only. However, molecular relapses of CML after transplant were only safely detectable when a nested real-time PCR assay was performed, which was able to detect 1-10 pg cDNA from a tenfold serial dilution. The median normalized BCR-ABL transcript level was measured as 0.004% in 17 patients with a molecular relapse, 0.4% in 7 patients with a cytogenetic relapse, 2.6% in 36 patients with a stable phase of CML, and 36% in 5 patients with a relapse in a blast crisis. The analyzed median normalized amount of BCR-ABL transcript differed significantly (P<0.001) between the various disease stages. In ten CML patients with relapse, the real-time PCR method was used to monitor the response of various immunotherapies as donor leukocyte infusions, withdrawal of immunosuppression, or interferon-alpha application. The results of the quantitative evaluation of BCR-ABL transcripts reflected very well the clinical effect of the different applied immunotherapies. The new real-time PCR method seems to be a suitable technique for the early detection of relapse after allogeneic transplant in patients with the BCR-ABL transcript. Its ability to distinguish between molecular and cytogenetic relapse (P<0.001) allows early therapeutic decisions.

Bone Marrow Transplantation↗
PubMed2001

Predominantly BCR-ABL negative myeloid precursors in interferon-alpha treated chronic myelogenous leukemia: a follow-up study of peripheral blood colony-forming cells with fluorescence in situ hybridization.

The mechanism and target cell of the life-prolonging effect of interferon-alpha (IFN-alpha) in chronic myelogenous leukemia (CML) are controversial. We studied the influence of IFN-alpha treatment on the frequency of malignant hematopoietic precursor cells in the peripheral blood (PB) of CML patients during the course of the disease. PB 10-day colony-forming cells (PB-CFCs) were assessed with regard to their quantity, lineage distribution, and BCR-ABL status, as determined by fluorescence in situ hybridization (FISH). PB-CFC numbers were determined in 39 patients (29 in the chronic phase, 6 in an advanced stage, and 4 with progression to an advanced stage during follow-up). Thirty-one patients were evaluated either once or several times to determine the BCR-ABL status of the colonies. BCR-ABL negative PB-CFCs were detectable at diagnosis in 5 of 11 patients. A major reduction of BCR-ABL positive colonies to <25% of PB-CFCs was observed in 10/13 determinable IFN-alpha treated patients in early and late chronic phases, indicating a high proportion of BCR-ABL negativity at the clonogenic cell level. In contrast, only 3 of these patients had a cytogenetic response of <25% Philadelphia chromosome (Ph1)-positive metaphases in bone marrow cytogenetics. Treatment with IFN-alpha and/or hydroxyurea (HU) during chronic phase was accompanied by a reduction of PB-CFCs to subnormal levels (median 24 CFCs/ml) compared to controls (median 207 CFCs/ml), untreated patients in chronic phase (median 25,979 CFCs/ml), and patients with advanced disease (median 6,047 CFCs/ml). In blast crisis (6 patients), all colonies tested were BCR-ABL positive. Our results show that IFN-alpha treatment leads to a marked reduction of malignant myeloid precursor cells in the PB of CML patients, which exceeds the degree of cytogenetic remission. This offers an explanation for the good therapeutic efficacy and even life-prolonging effect of IFN-alpha, which is also observed in cytogenetic non-responders.

Fusion Proteins, bcr-abl↗
PubMed2005

BCR-ABL gene amplification and overexpression in a patient with chronic myeloid leukemia treated with imatinib.

Imatinib mesylate was designed as an inhibitor targeting the BCR-ABL tyrosine kinase, the molecular counterpart of the Philadelphia translocation t(9;22)(q34;q11). We report on a patient with chronic myeloid leukemia (CML) undergoing acceleration during imatinib treatment. Cytogenetic analysis revealed four different cell populations: 46,XX,t(9;22)(q34;q11),der(18)t(2;18)(p11;p11)[1]/47,idem,i(17)(q10),-der(18)t(2;18),+der(22)t(9;22)[1]/46,idem,-t(9;22),der(9)t(9;22),ider(22)t(9;22)[12]/ 47,idem,-t(9;22),der(9)t(9;22),+22,ider(22)t(9;22)x2[1]. FISH analysis confirmed the presence of these four clones. Moreover, 49% of the interphase nuclei contained either one or two clustered fusion signals, indicating a low-level amplification of the BCR-ABL fusion gene. With quantitative real-time RT-PCR, a BCR-ABL/G6PDH ratio of 0.8 was determined, which is comparable to that measured in the K562 cell line with a known BCR-ABL amplification and which is increased by more than about 60-fold compared to a CML at diagnosis with >80% Philadelphia-positive cells. We give further evidence that the genomic BCR-ABL amplification results in an increased level of BCR-ABL transcript linking two potent mechanisms of resistance against imatinib treatment.

Aged↗
PubMed2004

Differences and similarities in kinetics of BCR-ABL transcript levels in CML patients treated with imatinib mesylate for chronic or accelerated disease phase.

Kinetics of BCR-ABL transcript levels were determined in 19 patients with chronic myeloid leukemia (CML) treated with imatinib for chronic (CP) or accelerated phase (AP). Patients could be divided into three groups with: (1) a sharp and sustained decrease in BCR-ABL transcript level reaching 0.1-0.002% (only CP); (2) an early BCR-ABL overexpression up to 2500% (only AP); and (3) a stable trend with BCR-ABL values between 10 and 100% (CP, AP). In group 1, relapses were not developed within the follow-up; in group 2, patients progressed to blast crisis; in group 3, BCR-ABL overexpression appeared after 12 months in some patients and disease relapses were found 2-16 weeks later. It is summarized that BCR-ABL transcript kinetics clearly characterize responses to imatinib treatment and are highly predictive for disease progression.

Adult↗