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PubMed1991

[Philadelphia-positive ALL with rearrangement of the 1st intron of the BCR gene].

We have studied the haematologic, cytogenetic and molecular features in a patient with Ph positive ALL. The cytogenetic study showed the presence of a Ph chromosome since diagnosis. Molecular analysis showed rearrangement within the first intron of bcr gen instead of M-bcr as in CML. This an evidence of genic fusion between c-abl oncogene and bcr gene and also show the possibility of rearrangement outside M-bcr in these patients.

Aged↗
PubMed1990

A novel variant of the bcr-abl fusion product in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Two patients with Philadelphia chromosome-positive acute lymphoblastic leukemia showed novel variants of the chimeric bcr-abl mRNA. The bcr-abl breakpoint region on cDNA derived from the chimeric mRNA was amplified using the polymerase chain reaction (PCR). Sequence analysis of the breakpoint-containing fragment showed that in both patients exon a2 of the abl gene was deleted, giving rise to an in-frame joining at the mRNA level of 5' bcr sequences to the abl exon a3. These findings were confirmed by Southern blot analysis and cloning of chromosomal DNA. Protein studies showed a bcr-abl protein with heightened tyrosine kinase activity in blast cells of both patients: one of the P190 type, the other of the P210 type. The significance of these findings and the role of this new type of translocation in the disregulation of the abl gene are discussed.

Adult↗
PubMed1989

bcr rearrangement: potential false positive secondary to an Eco RI restriction fragment length polymorphism.

Molecular studies have demonstrated that the Philadelphia chromosome (Ph) translocation characteristic of chronic granulocytic leukemia (CGL) and 50% of the cases of Ph positive acute lymphocytic leukemia (ALL) involves a limited 5.8 Kb region on chromosome 22 termed the breakpoint cluster region (bcr). Detection of bcr rearrangement by Southern blot analysis has proven to be a sensitive diagnostic method and can identify this translocation in some cases which appear cytogenetically negative. Restriction fragment length polymorphisms (RFLP) which involve bcr have the potential to be misinterpreted as gene rearrangements since they result in alteration of the DNA fragment size detected by Southern blot hybridization. We have identified a RFLP involving bcr that is detectable with Eco RI digestion but not with Bam HI, BgI II, or Xba I. The polymorphic fragments generated indicate that this RFLP is the result of an Eco RI restriction site sequence polymorphism.

Adult↗
PubMed1989

[BCR rearrangement and cytogenetic findings in Philadelphia-positive chronic myelocytic leukemia in children].

Eight children with Philadelphia (Ph1) chromosome positive chronic myelocytic leukemia (CML) were available for cytogenetic studies and breakpoint cluster region (bcr) rearrangement analysis as compared to the features of adults with Ph1-positive CML. In chronic phase additional abnormalities other than Ph1 chromosome were found in none of our cases. On the other hand, in blastic crisis all of 6 cases had additional chromosomal abnormalities like as i(17q), double Ph1 and +8. The frequency of the appearance of additional chromosomal abnormalities, especially i(17q), is higher in children than in adult cases. In the DNA of 7 of 7 examined patients, rearrangement of bcr could be demonstrated by Southern blot analysis. These findings were similar to those observed in adults. An analysis of the location of the bcr breakpoint indicated that 5' breakpoints were found in four cases who were long-term survivors, and two of the other cases had blastic crisis from the onset of the disease. These findings showed the cytogenetic findings of children with Ph1+CML were different from those of the adult cases in the frequency of the appearance of the additional chromosomal abnormalities, and the location of the bcr breakpoint in children cases might be different from that in the adult cases and influence its prognosis.

Adolescent↗
PubMed1988

The location of breakpoints within the breakpoint cluster region (bcr) of chromosome 22 in chronic myeloid leukemia.

Rearrangement of the breakpoint cluster region (bcr) was demonstrated by Southern blot analysis in the DNA in each of 68 patients with Ph chromosome-positive CML and in 3 of 7 patients with apparent Ph chromosome-negative CML. In contrast, no bcr rearrangement could be found in DNA from 17 normal individuals and 28 patients with various hematologic disorders other than CML or ALL. An analysis of the location of the breakpoints within the bcr indicated that 3' breakpoints were significantly more common in patients in blast crisis or accelerated phase disease compared to those with chronic phase disease. Patients with chronic phase disease and 3' breakpoints had shorter average disease duration than that for chronic phase patients with 5' breakpoints, although the difference between these two groups of patients was not statistically significant. For patients who had progressed to accelerated disease or blast crisis, a statistically significant difference in chronic phase disease duration could be demonstrated between 11 patients with 3' breakpoints (average chronic phase 30.2 months) and 15 patients with 5' breakpoints (average chronic phase 50.6 months). For 8 patients studied in both chronic phase and accelerated or blast crisis, the location of the breakpoint did not change. We suggest that the bcr-abl fusion protein associated with a 3' breakpoint could result in more rapid progression to acute disease, and this may account for differences in the relative frequency of 3' and 5' breakpoints at different disease stages. Although more studies are required, identifying CML patients with a higher propensity for early blast transformation may eventually prove to be of some clinical value.

Blast Crisis↗
PubMed1995

Optimization of antisense oligodeoxynucleotide structure for targeting bcr-abl mRNA.

Antisense oligodeoxynucleotides targeted to bcr-abl are potential ex vivo purging agents for use with autologous bone marrow transplantation in the treatment of chronic myeloid leukemia (CML). We investigated, in a cell-free system, the activity and nuclease resistance of phosphodiester, phosphorothioate, chimeric methylphosphonate/phosphodiester, and chimeric methylphosphonate/phosphorothioate antisense octadecamers directed against either b2a2 or b3a2 bcr-abl breakpoint RNAs. Certain chimeric compounds were shown to possess targeted activity broadly equal to the parent phosphodiester or phosphorothioate forms and greater resistance to the nucleases present in cell extracts. Selected chimeric structures were compared with phosphodiester and phosphorothioate analogues for antisense activity in human CML cells containing either b2a2 or b3a2 bcr-abl breakpoint mRNAs. We present results showing that all four structures can suppress bcr-abl mRNA level in vivo. The rank of in vivo activity is chimeric methylphosphonate/phosphodiester > or = phosphodiester > phosphorothioate > methylphosphonate/phosphorothioate. We show that b2a2 breakpoint RNAs can be more effectively targeted than b3a2 sequence RNAs both in vitro and in vivo and suggest that RNA secondary structure may be a possible explanation for this phenomenon.

Base Sequence↗
PubMed1999

The nuclear topography of ABL, BCR, PML, and RARalpha genes: evidence for gene proximity in specific phases of the cell cycle and stages of hematopoietic differentiation.

The mechanisms whereby chromosomal translocations are consistently associated with specific tumor types are largely unknown. A generally accepted hypothesis is that the physical proximity of the involved chromosomal regions may be one important factor in the genesis of these phenomena. Accordingly, a likely possibility is that such a proximity may occur in a cell-lineage and cell-differentiation stage-specific manner. In this work, we have addressed this issue using as models the ABL and BCR genes of t(9;22) and the PML and RARalpha genes of t(15;17). By using in situ hybridization and confocal microscopy, we have measured the distances between these two pairs of genes in three-dimensionally preserved hematopoietic cells belonging to different cell lineages, at various stages of differentiation, and at various stages of the cell cycle, with the following results. (1) Intergenic distances vary periodically during the cell cycle and a significant association of ABL with BCR and of PML with RARalpha is seen at the transition between S and G2, which persists during G2 and prophase (such a behavior is not observed for distances between ABL or PML and the beta-globin genes, used as a control). (2) The proportion of cells in which PML and RARalpha or ABL and BCR are closely associated is higher in hematopoietic precursors than in B-lymphoid cells (whereas the distances between ABL or PML and the beta-globin genes are not affected by cell type). (3) When intergenic distances in unstimulated bone marrow CD34(+) cells were compared with those in CD34(+) cells treated with interleukin-3 (IL-3), a trend towards a higher proximity of the ABL and BCR genes in the former and of the PML and RARalpha genes in the latter is observed. (4) Analysis of B-lymphoid cells during mitosis shows that intergenic distances at metaphase are strongly influenced by physical constraints imposed by the chromosomal location of the gene, by the size of the respective chromosome, and by the geometry of the metaphase plate. These findings suggest that intrinsic spatial dynamics, established early in hematopoiesis and perpetuated differentially in distinct cell lineages, may facilitate the collision of individual genes and thus reciprocal recombination between them at subsequent stages of hematopoietic differentiation.

Cell Cycle↗
PubMed2026

Dual functional genomics reveals a broad and convergent landscape of asciminib resistance in BCR::ABL1.

BACKGROUND: Drug resistance is a constantly evolving challenge. The allosteric inhibitor asciminib is a novel therapy for chronic myelogenous leukemia (CML) that targets the myristoyl pocket of the BCR::ABL1 kinase. While it can overcome resistance to active-site inhibitors like imatinib, new resistance mutations to asciminib are emerging. The complete landscape of these mutations, particularly those outside the kinase domain or those arising from epistatic interactions between mutations, are not well understood. METHODS: This study employed a dual functional genomics approach in CML cell line models. A high-throughput adenosine base editing (ABE) screen was used to identify broad hotspots of asciminib resistance across the entire BCR::ABL1 protein. Deep mutational scanning (DMS) was then used to create a high-resolution map of all possible amino acid changes within these hotspots. An "edit-on-edit" screen was performed to investigate epistasis by introducing a library of mutations into a cell line that was pre-edited to incorporate the common imatinib-resistance mutation, Y253H. Finally, a novel Förster resonance energy transfer (FRET) biosensor was developed to measure the conformational state of BCR::ABL1 in live cells and link it to drug sensitivity. RESULTS: The screens identified 279 asciminib resistance mutations and revealed resistance hotspots distributed across the SH3, SH2, and kinase domains, in contrast to imatinib resistance, which is largely confined to the kinase domain. The study uncovered a potent epistatic interaction between a mutation in the SH3 domain (V73A) and a mutation in the kinase domain P-loop (Y253H), which synergistically conferred high-level resistance. The FRET biosensor demonstrated that asciminib resistance mutations tend to destabilize the "closed" inactive conformation of the ABL1 kinase. CONCLUSIONS: The landscape of asciminib resistance is broader and more complex than previously appreciated, involving mutations across multiple domains that disrupt ABL1 autoinhibition. Epistasis between mutations acquired during sequential therapies can create unexpected and potent resistance. However, these diverse genetic resistance mechanisms converge on a single biophysical measurement of the openness of the active ABL1 conformation. This provides a unified framework for understanding asciminib resistance and underscores the need for routine clinical resistance monitoring to include the SH3 and SH2 domains in first line and later line therapy.

Fusion Proteins, bcr-abl↗
PubMed1990

Detection of bcr-abl fusion in chronic myelogeneous leukemia by in situ hybridization.

Chronic myelogeneous leukemia (CML) is genetically characterized by fusion of the bcr and abl genes on chromosomes 22 and 9, respectively. In most cases, the fusion involves a reciprocal translocation t(9;22)(q34;q11), which produces the cytogenetically distinctive Philadelphia chromosome (Ph1). Fusion can be detected by Southern (DNA) analysis or by in vitro amplification of the messenger RNA from the fusion gene with polymerase chain reaction (PCR). These techniques are sensitive but cannot be applied to single cells. Two-color fluorescence in situ hybridization (FISH) was used with probes from portions of the bcr and abl genes to detect the bcr-abl fusion in individual blood and bone marrow cells from six patients. The fusion event was detected in all samples analyzed, of which three were cytogenetically Ph1-negative. One of the Ph1-negative samples was also PCR-negative. This approach is fast and sensitive, and provides potential for determining the frequency of the abnormality in different cell lineages.

Chromosomes, Human, Pair 22↗
PubMed2002

The coiled-coil domain and Tyr177 of bcr are required to induce a murine chronic myelogenous leukemia-like disease by bcr/abl.

The bcr/abl fusion in chronic myelogenous leukemia (CML) creates a chimeric tyrosine kinase with dramatically different properties than intact c-abl. In P210 bcr/abl, the bcr portion includes a coiled-coil oligomerization domain (amino acids 1-63) and a grb2-binding site at tyrosine 177 (Tyr177) that are critical for fibroblast transformation, but give variable results in other cell lines. To investigate the role of the coiled-coil domain and Tyr177 in promoting CML, 4 P210 bcr/abl-derived mutants containing different bcr domains fused to abl were constructed. All 4 mutants, Delta(1-63) bcr/abl, (1-63) bcr/abl, Tyr177Phe bcr/abl, and (1-210) bcr/abl exhibited elevated tyrosine kinase activity and conferred factor-independent growth in cell lines. In contrast, differences in the transforming potential of the 4 mutants occurred in our mouse model, in which all mice receiving P210 bcr/abl-expressing bone marrow cells exclusively develop a myeloproliferative disease (MPD) resembling human CML. Of the 4 mutants assayed, only 1-210 bcr/abl, containing both the coiled-coil domain and Tyr177, induced MPD. Unlike full-length P210, this mutant also caused a simultaneous B-cell acute lymphocytic leukemia (ALL). The other 3 mutants, (1-63) bcr/abl, Tyr177Phe bcr/abl, and Delta(1-63) bcr/abl, failed to induce an MPD but instead caused T-cell ALL. These results show that both the bcr coiled-coil domain and Tyr177 are required for MPD induction by bcr/abl and provide the basis for investigating downstream signaling pathways that lead to CML.

Animals↗
PubMed2003

Mercury determination in solid phases from application of the modified BCR-sequential extraction procedure: a valuable tool for assessing its mobility in sediments.

The present paper presents a feasibility study for the evaluation of mercury mobility in sediments by application of the modified BCR three-step sequential extraction procedure (BCR-SEP). The aim of the study was to evaluate the effect of acidification, reduction and oxidation processes on mercury mobility from sediments, once the SEP was validated with other trace metals. As extractable mercury amounts were mostly found below detection limits of the advanced mercury analyser (AMA-254) used for measuring the extracts (L.D.<0.5 ng), the use of a solid sampling atomic absorption spectrometer with a specially designed furnace for Hg atomisation was found to be an optimal technique to quantify Hg in the solid residues coming from the SEP. With this approach, mercury was found to be hardly mobile and only for one of the moderately polluted sediments (BCR CRM 320), extractable mercury (exchangeable fraction, BCR procedure step 1) has been found. An oxidation step with H(2)O(2) was required to obtain extractability up to 64% of the total content in a highly polluted lagoon sediment.

Chemical Fractionation↗
PubMed1984

Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22.

We have identified and molecularly cloned 46 kb of human DNA from chromosome 22 using a probe specific for the Philadelphia (Ph') translocation breakpoint domain of one chronic myelocytic leukemia (CML) patient. The DNAs of 19 CML patients were examined for rearrangements on chromosome 22 with probes isolated from this cloned region. In 17 patients, chromosomal breakpoints were found within a limited region of up to 5.8 kb, for which we propose the term "breakpoint cluster region" (bcr). The two patients having no rearrangements within bcr lacked the Ph' chromosome. The highly specific presence of a chromosomal breakpoint within bcr in Ph'-positive CML patients strongly suggests the involvement of bcr in this type of leukemia.

Bacterial Proteins↗
PubMed1988

Myelodysplastic syndrome with Philadelphia-like chromosome without bcr rearrangement.

The case of a 62-year-old Japanese male with a myelodysplastic syndrome and a Philadelphia (Ph)-like chromosome, which probably involved bands 11q23 and 22q11, is presented. Cytogenetic analysis of bone marrow cells revealed a Ph chromosome as well as -5, -7, +8, +11, -16, and an extra Ph. Some of the cells had a normal karyotype. Molecular analysis using breakpoint cluster region probes (5' bcr and 3' bcr) did not detect a rearrangement within the bcr DNA sequences, indicating that the breakpoint at 22q11 occurred outside the bcr. Furthermore, the bone marrow cells from this patient did not express an 8.5-kb c-abl mRNA. Thus, the Ph chromosome in this case differs from that of Ph-positive chronic myelogenous leukemia, and the present case suggests that we should retain the term of "Ph-like chromosome" in such cases.

Anemia, Refractory, with Excess of Blasts↗
PubMed2006

Fractionation of metals in street sediment samples by using the BCR sequential extraction procedure and multivariate statistical elucidation of the data.

The concentrations of metals (Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, and Zn) in street sediment samples were determined by flame atomic absorption spectrometry (FAAS) using the modified BCR (the European Community Bureau of Reference) sequential extraction procedure. According to the BCR protocol for extracting the metals from the relevant target phases, 1.0 g of specimen of the sample was treated with 0.11 M acetic acid (exchangeable and bound to carbonates), 0.5M hydroxylamine hydrochloride (bound to iron- and manganese-oxides), and 8.8M hydrogen peroxide plus 1M ammonium acetate (bound to sulphides and organics), sequentially. The residue was treated with aqua regia solution for recovery studies, although this step is not part of the BCR procedure. The mobility sequence based on the sum of the BCR sequential extraction stages was: Cd approximately Zn ( approximately 90%)>Pb ( approximately 84%)>Cu ( approximately 75%)>Mn ( approximately 70%)>Co ( approximately 57%)>Ni ( approximately 43%)>Cr ( approximately 40%)>Fe ( approximately 17%). Enrichment factors as the criteria for examining the impact of the anthropogenic emission sources of heavy metals were calculated, and it was observed that the highest enriched elements were Cd, Pb, and Zn in the dust samples, average 190, 111, and 20, respectively. Correlation analysis (CA) and principal component analysis (PCA) were applied to the data matrix to evaluate the analytical results and to identify the possible pollution sources of metals. PCA revealed that the sampling area was mainly influenced from three pollution sources, namely; traffic, industrial, and natural sources. The results show that chemical sequential extraction is a precious operational tool. Validation of the analytical results was checked by both recovery studies and analysis of the standard reference material (NIST SRM 2711 Montana Soil).

Automobiles↗
PubMed2003

Changes in bad phosphorylation are correlated with BCR-induced apoptosis of WEHI-231 immature B cells.

Signaling through the B cell antigen receptor (BCR) is a key determinant in the regulation of B cell physiology. Depending on additional factors, such as microenvironment and developmental stage, ligation of the BCR can trigger B lymphocyte activation, proliferation, or apoptosis. The regulatory mechanisms determining B cell apoptosis and survival are not completely known. Using the murine B lymphoma cell line WEHI-231 as a model system, we investigated the role of Bad phosphorylation, a pro-apoptotic member of the Bcl-2 family, in anti-IgM mediated apoptosis. For apoptotic analysis we focused in particular on the mitochondrial potential (deltapsi(m)) collapse which has been reported as a rate-limiting step in the BCR-induced cell death of immature B lymphocytes. Bad phosphorylation at serine 112, 136 and 155 was found in WEHI-231 cell control cultures and its hypophosphorylation on the three sites correlated with the appearance of apoptosis when cross-linking surface IgM. Furthermore, treatment of cells with specific PK inhibitors known to be involved in serine phosphorylation of Bad (LY294002 for PI3K and H-89 for PKA) mimiced or enhanced BCR-induced cell death. These results strongly suggest that regulation of Bad phosphorylation plays an active role in mediating anti-IgM-induced apoptosis of immature B cells.

14-3-3 Proteins↗
PubMed2004

FcgammaRIIb-mediated negative regulation of BCR signalling is associated with the recruitment of the MAPkinase-phosphatase, Pac-1, and the 3'-inositol phosphatase, PTEN.

The low-affinity receptor for IgG, FcgammaRIIb, negatively regulates B cell antigen receptor (BCR)-mediated proliferative signalling. FcgammaRIIb has been reported to mediate this inhibition by uncoupling the BCR from the RasMAPkinase pathway. We now show that FcgammaRIIb-mediated negative feedback inhibition also correlates with induction of an Erk-associated phosphatase activity that reflects the rapid association of Erk and the MAPkinase phosphatase, Pac-1, and dephosphorylation and inactivation of ErkMAPkinase. This mechanism of abrogating ongoing ErkMAPkinase signalling therefore provides a rationale for rapid immune-complex-mediated feedback inhibition of active antigen-driven B cell responses. In addition, FcgammaRIIb signalling also induces the recruitment and activation of the 3'-inositol phosphatase, PTEN, which by antagonising PI 3kinase activity and inhibiting BCR-coupling to the anti-apoptotic kinase, Akt, provides an additional mechanism for FcgammaRIIb-mediated negative regulation of BCR-coupling to ErkMAPkinase, cell survival and proliferation.

Animals↗
PubMed1997

BCR ligation induces receptor editing in IgM+IgD- bone marrow B cells in vitro.

The ability of BCR cross-linking to stimulate receptor editing was analyzed in vitro using bone marrow B cells from immunoglobulin (Ig) transgenic (Tg) and non-Tg mice. In cultured Ig-Tg cells, BCR ligation induced receptor editing as measured by up-regulation of RAG gene expression, light chain gene DNA rearrangements, and expression of lambda-light chain protein in cells that previously expressed kappa. In the culture conditions used, BCR ligation induced light chain rearrangements in most immature IgM+IgD- bone marrow B cells in the absence of significant cell death or cell growth. Receptor editing in non-Tg B cells was also documented in cultures treated with anti-immunoglobulin. These results provide direct evidence for the ability of BCR ligation to stimulate immunoglobulin light chain gene rearrangements in immature B cells.

Animals↗
PubMed2002

Control of pre-BCR signaling by Pax5-dependent activation of the BLNK gene.

The developmental progression from pro-B to pre-B cells is controlled by pre-B cell receptor (pre-BCR) signaling which depends on BLNK (SLP-65) for coupling the Syk kinase to its downstream effector pathways. Here we identified BLNK as a direct target of the transcription factor Pax5 (BSAP). Restoration of BLNK expression in Ig(mu) transgenic Pax5(-/-) pro-B cells resulted in constitutive pre-BCR signaling and increased cell proliferation without inducing progression to the pre-B cell stage. Ig(mu)(+) Pax5(-/-) pro-B cells expressing a BLNK-estrogen receptor fusion protein initiated signaling immediately upon hormone addition, which facilitated analysis of pre-BCR-induced gene expression changes. The pre-BCR was shown to execute its checkpoint function by regulating genes involved in cell proliferation, intracellular signaling, growth factor responsiveness, and V(D)J recombination.

Adaptor Proteins, Signal Transducing↗