Alternative titles; symbols
Other entities represented in this entry:
HGNC Approved Gene Symbol: BCR
Cytogenetic location: 22q11.23 Genomic coordinates (GRCh38): 22:23,180,509-23,318,037 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q11.23 | Leukemia, acute lymphocytic, Philadelphia chromosome positive, somatic | 613065 | 4 | |
| Leukemia, chronic myeloid, Philadelphia chromosome positive, somatic | 608232 | 4 |
The normal cellular BCR gene encodes a 160-kD phosphoprotein associated with serine/threonine kinase activity. The BCR gene is the site of breakpoints used in the generation of the 2 alternative forms of the Philadelphia chromosome translocation found in chronic myeloid leukemia (CML; 608232) and acute lymphocytic leukemia (Groffen et al., 1984; Shtivelman et al., 1985; Hermans et al., 1987). These alternative breakpoints join different exon sets of BCR to a common subset of the exons of the ABL1 gene (189980) located on chromosome 9. This fusion results in 2 alternative chimeric oncogene products called p210(BCR-ABL) and p185(BCR-ABL). The activation of ABL tyrosine kinase activity is necessary for the oncogenic potential of the chimeric oncogene (Maru and Witte, 1991).
Laurent et al. (2001) reviewed the role of BCR alone or when joined with ABL in normal and leukemic pathophysiology.
Hariharan and Adams (1987) isolated cDNA clones that spanned the entire BCR coding region. The deduced 1,271-residue protein has a molecular mass of about 160 kD. The BCR gene is expressed as mRNAs of 4.5- and 6.7-kb, which apparently encode the same protein.
Stam et al. (1987) showed that the normal gene on chromosome 22 involved at the breakpoint cluster region in the translocation between chromosomes 9 and 22 encodes a 160,000-Da phosphoprotein with serine or threonine kinase activity.
Chissoe et al. (1995) sequenced the complete BCR gene and greater than 80% of the human ABL gene, which are both involved in the t(9;22) translocation (Philadelphia chromosome) associated with more than 90% of CML, 25 to 30% of adult and 2 to 10% of childhood acute lymphoblastic leukemia, and rare cases of acute myelogenous leukemia.
Heisterkamp et al. (1985) determined the structural organization of the BCR gene, which contains 23 exons and occupies a region of about 135 kb on chromosome 22. The first exon contains a unique serine/threonine kinase activity and at least 2 SH2 binding sites.
Stam et al. (1987) demonstrated that the BCR gene is oriented with its 5-prime end toward the centromere of chromosome 22.
Chissoe et al. (1995) determined that the BCR gene contains 23 BCR exons with putative alternative BCR first and second exons.
The BCR gene is located on chromosome 22q11.2, the site of the translocation breakpoint in CML (Prakash and Yunis, 1984).
Croce et al. (1987) demonstrated that there are in fact 4 BCR genes, all located in the 22q11.2 band. By studying mouse-human hybrid cells with breakpoints at various sites in that region, they concluded that the order of loci is centromere--BCR2, BCR4, IGL--BCR1--BCR3--SIS. This linear order was confirmed by Budarf et al. (1988), who also confirmed that all of the BCR-like genes (BCRL2, BCRL3, and BCRL4) map proximal to the 22q11-q12 breakpoint of a t(11;22) in a Ewing sarcoma (612219).
Using an interspecific backcross, Justice et al. (1990) mapped the Bcr gene to chromosome 10 of the mouse.
Maru and Witte (1991) demonstrated that purified BCR contains autophosphorylation activity and transphosphorylation activity for several protein substrates. A region encoded by the first exon was essential for this novel phosphotransferase activity. The findings suggested that the protein kinase and SH2-binding domains may work in concert with other regions of the molecule in intracellular signaling processes.
Diekmann et al. (1991) found that the C-terminal domain of BCR functions as a GTPase activating protein for p21(rac); see rac serine/threonine protein kinase (164730).
BCR/ABL Fusion Gene
Nowell and Hungerford (1960) identified the Philadelphia chromosome of chronic myeloid leukemia (a G group chromosome with part of its long arm missing). It was called the Philadelphia chromosome because it was thought to be useful to follow the practice of hemoglobinologists and name anomalous chromosomes after the city of discovery. It was presumed to be a deleted chromosome 21, the same chromosome as that which is trisomic in Down syndrome (190685). The elevated alkaline phosphatase activity in Down syndrome and depressed activity in CML was viewed as consistent with this interpretation. Using the improved definition provided by 'banding' methods, Rowley (1973) showed that in fact there is a translocation of the distal part of chromosome 22 (not 21) onto another chromosome, usually 9q.
Fitzgerald (1976) described a family in which a man and 2 of his 3 children had a Philadelphia-like chromosome t(11;22)(q25;q13). The fact that they did not have leukemia or other hematologic disorder was thought by Fitzgerald to relate to the finding that the break in chromosome 22 was distal to that in CML. In these cases it was at the q12-q13 interface, whereas in the Philadelphia chromosome it is at the q11-q12 band interface. Thus the 22q12 band may contain critical genetic material concerned with normal (and abnormal) myeloid proliferation.
De Klein et al. (1982) demonstrated that the Abelson oncogene is translocated from chromosome 9 to chromosome 22 in the formation of the Philadelphia chromosome.
Prakash and Yunis (1984) located the breakpoints in CML to subbands 22q11.21 and 9q34.1. Although the position of the breakpoint in chromosome 9 is quite variable, the breakpoint in chromosome 22 is clustered in an area called bcr for 'breakpoint cluster region.' Shtivelman et al. (1985) referred to bcr as a gene and stated that the ABL oncogene is transferred 'into the bcr gene of chromosome 22.' They found that an 8-kb RNA specific to CML is a fused transcript of the 2 genes. The fused protein is presumably involved in the malignant process. The protein has bcr information at its amino terminus and retains most but not all of the normal abl protein sequences. Since the breakpoint in 9 may be as much as 30 or 40 kb 5-prime to ABL, a large amount must be 'looped out' in the fusion process. The fusion protein has tyrosine kinase activity.
About 10% of patients with acute lymphocytic leukemia (ALL) have the translocation t(9;22)(q34;q11) indistinguishable from that of CML (608232). Erikson et al. (1986), however, found in 3 of 5 such cases of ALL that the bcr region was not involved and that the 22q11 chromosome breakpoint was proximal (5-prime) to the bcr region. Furthermore, the bcr and c-abl transcripts were of normal size in an ALL line carrying the t(9;22) translocation. The breakpoints of the t(9;22) CML, the t(9;22) of acute lymphocytic leukemia, and the t(8;22) of Burkitt lymphoma fall into 22q11 and are cytologically indistinguishable. By chromosomal in situ hybridization, however, they can be distinguished (Emanuel et al., 1984; Erikson et al., 1986). To this experience, Griffin et al. (1986) added observations on t(11;22), both constitutional and tumor-related (see 133450). In the hybrid gene of CML, the bcr contribution is 5-prime to the abl contribution. In the creation of the gene, splicing can occur across an interval as great as 100 kb. The product of the bcr/abl hybrid gene is a 210-kD protein. It was suggested that the hybrid gene and its product protein be designated PHL.
Mes-Masson et al. (1986) isolated overlapping cDNA clones defining the complete coding region for the hybrid protein generated from the ABL and BCR genes.
As a result of the CML translocation, the 3-prime BCR exons are removed and remain on chromosome 22 (Stam et al., 1987). The BCR and ABL genes are fused in a head-to-tail fashion.
Verhest and Monsieur (1983) found the Philadelphia chromosome in a case of essential thrombocytopenia.
Ganesan et al. (1986) found that the BCR gene was rearranged in 7 cases of Philadelphia chromosome-negative CML. In 5 cases hematologic findings were indistinguishable from those of patients with the Philadelphia chromosome.
Hermans et al. (1987) showed that a distinct and different fusion of BCR and ABL occurs in creation of the Philadelphia chromosome associated with acute lymphoblastic leukemia (ALL). Rubin et al. (1988) similarly reported a distinctive fusion in ALL.
Haas et al. (1992) demonstrated a 'parent of origin' bias in cases of Philadelphia chromosome-positive leukemia by use of unique specific chromosome band polymorphisms. They showed that the translocated chromosome 9 was always of paternal origin, whereas the translocated chromosome 22 was derived exclusively from the maternal copy. Preferential retention of paternal alleles has been found in sporadic tumors such as Wilms tumor (194070), rhabdomyosarcoma (268210), osteosarcoma (259500), and retinoblastoma (180200). The finding of preferential participation of the paternally derived chromosome 9 and the maternally derived chromosome 22 in the Ph-translocation strongly indicates that the chromosomal regions involved are imprinted. Feinberg (1993) reviewed 11 examples of preferential parental allelic alterations in cancer. Fioretos et al. (1994) were unable to find evidence for genomic imprinting of the human BCR gene. They identified a BamHI polymorphism in the coding region of BCR exon 1 and by RT-PCR assay showed that both BCR alleles are expressed in the peripheral blood cells of normal persons. Furthermore, Litz and Copenhaver (1994) used PvuII and MaeII restriction site polymorphisms in the BCR gene to study 3 cases of Philadelphia chromosome-positive CML. In all 3 cases, the rearranged allele was paternal in origin. Melo et al. (1994) could find no evidence of parental imprinting of the ABL gene and cited evidence which appeared to exclude imprinting of the BCR gene and to suggest that there is, in fact, no preferential involvement of the maternal BCR or paternal ABL alleles in the formation of the BCR-ABL fusion gene. Melo et al. (1995) further reviewed the evidence they interpreted as indicating that there is no parental bias in the origin of the translocated ABL gene and no evidence for genomic imprinting of ABL in CML. On the other hand, Haas (1995) argued that it still remains likely that ABL and BCR are imprinted.
From the sequence of 4 newly studied Philadelphia chromosome translocations and a review of several other previously sequenced breakpoints, Chissoe et al. (1995) could discern no consistent breakpoint features. No clear-cut mechanism for Philadelphia chromosome translocation was evident.
To block BCR/ABL function, Lim et al. (2000) created a unique tyrosine phosphatase by fusing the catalytic domain of SHP1 (604630) to the ABL binding domain of RIN1 (605965), an established binding partner and substrate for c-ABL and BCR/ABL. This fusion construct binds to BCR/ABL in cells and functions as an active phosphatase. It effectively suppressed BCR/ABL function as judged by reductions in transformation of fibroblast cells, growth factor independence of hematopoietic cell lines, and proliferation of primary bone marrow cells. In addition, the leukemogenic properties of BCR/ABL in a murine model system were blocked by coexpression of the fusion construct. Expression of the construct also reversed the transformed phenotype of a human leukemia-derived cell line. These results appeared to have direct implications for leukemia therapeutics and suggested an approach to block aberrant signal transduction in other pathologies through the use of appropriately designed escort/inhibitors.
Saglio et al. (2002) found that a patient with a typical form of CML carried a large deletion on the derivative chromosome 9q+ and an unusual BCR-BCL transcript characterized by the insertion, between BCR exon 14 and ABL exon 2, of 126 bp derived from a region located on chromosome 9, 1.4 Mb 5-prime to ABL. This sequence was contained in a bacterial artificial chromosome (BAC), which in FISH experiments on normal metaphases was found to detect, in addition to the predicted clear signal at 9q34, a faint but distinct signal at 22q11.2, where the BCR gene is located, suggesting the presence of a large region of homology between the 2 chromosome regions. A BLAST analysis of the particular BAC sequence against the entire human genome revealed the presence of a stretch of homology, about 76 kb long, located approximately 150 kb 3-prime to the BCR gene, and containing the 126-bp insertion sequence. Evolutionary studies using FISH identified the region as a duplicon, which transposed from the region orthologous to human 9q34 to chromosome 22 after the divergence of orangutan from the human-chimpanzee-gorilla common ancestor about 14 million years ago. Saglio et al. (2002) noted that sequence analyses reported as part of the Human Genome Project had disclosed an unpredicted extensive segmental duplication in the human genome, and the impact of duplicons in triggering genomic disorders is becoming more and more apparent. The discovery of a large duplicon relatively close to the ABL and BCR genes and the finding that the 126-bp insertion is very close to the duplicon at 9q34 open the question of the possible involvement of the duplicon in the formation of the Philadelphia chromosome translocation.
The arrest of differentiation is a feature of chronic myelogenous leukemia cells both in myeloid blast crisis and in myeloid precursors that ectopically express the p210(BCR-ABL) oncoprotein. Related to the underlying mechanisms of this arrest of differentiation, Perrotti et al. (2002) showed that expression of BCR-ABL in myeloid precursor cells leads to transcriptional suppression of the gene encoding granulocyte colony-stimulating factor receptor (CSF3R; 138971), possibly through downmodulation of C/EBP-alpha (116897), the principal regulator of granulocytic differentiation. Expression of C/EBP-alpha protein is barely detectable in primary marrow cells taken from individuals affected with chronic myeloid leukemia in blast crisis. In contrast, CEBPA RNA is clearly present. Further experiments by Perrotti et al. (2002) indicated that BCR-ABL regulates the expression of C/EBP-alpha by inducing heterogeneous nuclear ribonucleoprotein E2 (PCBP2; 601210).
RNA interference (RNAi) is a highly conserved regulatory mechanism that mediates sequence-specific posttranscriptional gene silencing initiated by double-stranded RNA (dsRNA) (Fire, 1999). Fusion transcripts encoding oncogenic proteins may represent potential targets for a tumor-specific RNAi approach. Scherr et al. (2003) demonstrated that small interfering RNAs (siRNAs) against BCR-ABL specifically inhibited expression of BCR-ABL mRNA in hematopoietic cell lines and primary CML cells.
Goldman and Melo (2003) tabulated BCR-ABL substrates and diagrammed the signal-transduction pathways affected by BCR-ABL.
To define oncogenic lesions that cooperate with BCR-ABL1 to induce ALL, Mullighan et al. (2008) performed a genomewide analysis of diagnostic leukemia samples from 304 individuals with ALL, including 43 BCR-ABL1 B-progenitor ALLs and 23 CML cases. IKZF1, encoding the transcription factor Ikaros (603023), was deleted in 83.7% of BCR-ABL1 ALL, but not in chronic phase CML. Deletion of IKZF1 was also identified as an acquired lesion at the time of transformation of CML to ALL (lymphoid blast crisis). The IKZF1 deletions resulted in haploinsufficiency, expression of a dominant-negative Ikaros isoform, or the complete loss of Ikaros expression. Sequencing of IKZF1 deletion breakpoints suggested that aberrant RAG-mediated recombination (see 179615) is responsible for the deletions. Mullighan et al. (2008) concluded that genetic lesions resulting in the loss of Ikaros function are an important event in the development of BCR-ABL1 ALL.
Zhao et al. (2009) demonstrated that the loss of Smoothened (Smo; 601500), an essential component of the hedgehog pathway (see 600725), impairs hematopoietic stem cell renewal and decreases induction of chronic myelogenous leukemia (CML; 608232) by the BCR-ABL1 oncoprotein. Loss of Smo causes depletion of CML stem cells, which propagate the leukemia, whereas constitutively active Smo augments CML stem cell number and accelerates disease. As a possible mechanism for Smo action, Zhao et al. (2009) showed that the cell fate determinant Numb (603728), which depletes CML stem cells, is increased in the absence of Smo activity. Furthermore, pharmacologic inhibition of hedgehog signaling impairs not only the propagation of CML driven by wildtype BCR-ABL1, but also the growth of imatinib-resistant mouse and human CML. Zhao et al. (2009) concluded that hedgehog pathway activity is required for maintenance of normal and neoplastic stem cells of the hematopoietic system and raised the possibility that the drug resistance and disease recurrence associated with imatinib treatment of CML might be avoided by targeting this essential stem cell maintenance pathway.
Resistance of Bcr-Abl-positive leukemic stem cells (LSCs) to imatinib treatment in patients with chronic myeloid leukemia (CML; 608232) can cause relapse of disease and might be the origin for emerging drug-resistant clones. Dierks et al. (2008) identified Smo as a drug target in Bcr-Abl-positive LSCs. They showed that Hedgehog signaling is activated in LSCs through upregulation of Smo. While nullity for Smo does not affect long-term reconstitution of regular hematopoiesis, the development of retransplantable Bcr-Abl-positive leukemias was abolished in the absence of Smo expression. Pharmacologic Smo inhibition reduced LSCs in vivo and enhanced time to relapse after end of treatment. Dierks et al. (2008) postulated that Smo inhibition might be an effective treatment strategy to reduce the LSC pool in CML.
Using xenografting and DNA copy number alteration (CNA) profiling of human BCR-ABL1 lymphoblastic leukemia, Notta et al. (2011) demonstrated that genetic diversity occurs in functionally defined leukemia-initiating cells and that many diagnostic patient samples contain multiple genetically distinct leukemia-initiating cell subclones. Reconstructing the subclonal genetic ancestry of several samples by CNA profiling demonstrated a branching multiclonal evolution model of leukemogenesis, rather than linear succession. For some patient samples, the predominant diagnostic clone repopulated xenografts, whereas in others it was outcompeted by minor subclones. Reconstitution with the predominant diagnosis clone was associated with more aggressive growth properties in xenografts, deletion of CDKN2A (600160) and CDKN2B (600431), and a trend towards poorer patient outcome. Notta et al. (2011) concluded that their findings linked clonal diversity with leukemia-initiating cell function and underscored the importance of developing therapies that eradicate all intratumoral subclones.
BCR/FGFR1 Fusion Gene
Demiroglu et al. (2001) described 2 patients with a clinical and hematologic diagnosis of CML in chronic phase who had an acquired t(8;22)(p11;q11). They confirmed that both patients were negative for a BCR-ABL fusion gene and that both had an in-frame mRNA fusion between BCR exon 4 and FGFR1 (136350) exon 9. Thus, a BCR-FGFR1 fusion may occur in patients with apparently typical CML. The possibility of successful treatment with specific FGFR1 inhibitors was suggested.
BCR/PDGFRA Fusion Gene
Baxter et al. (2002) reported the identification and cloning of a rare variant translocation, t(4;22)(q12;q11), in 2 patients with a CML-like myeloproliferative disease. An unusual in-frame BCR/PDGFRA (173490) fusion mRNA was identified in both patients, with either BCR exon 7 or exon 12 fused to short BCR intron-derived sequences, which were in turn fused to part of PDGFRA exon 12. Sequencing of the genomic breakpoint junctions showed that the chromosome 22 breakpoints fell in BCR introns, whereas the chromosome 4 breakpoints were within PDGFRA exon 12.
Resistance to Tyrosine Kinase Inhibitors
Clinical studies with the Abl tyrosine kinase inhibitor STI571 in CML demonstrated that many patients with advanced-stage disease respond initially but then relapse. Through biochemical and molecular analysis of clinical material, Gorre et al. (2001) found that the drug resistance was associated with a reactivation of BCR-ABL signal transduction in all cases examined. In 6 of 9 patients, resistance was associated with a single amino acid substitution in a threonine residue of the Abl kinase domain known to form a critical hydrogen bond with the drug. This substitution (T315I; 189980.0001) was sufficient to confer STI571 resistance in a reconstitution experiment. In 3 patients, resistance was associated with progressive BCR-ABL gene amplification. Gorre et al. (2001) concluded that their studies provided evidence that genetically complex cancers retain dependence on an initial oncogenic event and suggested a strategy for identifying inhibitors of STI571 resistance.
Azam et al. (2003) stated that sequencing of the BCR-ABL gene in patients who relapsed after STI571 chemotherapy revealed a limited set of kinase domain mutations that mediate drug resistance. To obtain a more comprehensive survey of the amino acid substitutions that confer STI571 resistance, they performed an in vitro screen of randomly mutagenized BCR-ABL and recovered all the major mutations previously identified in patients and numerous others that illuminated novel mechanisms of acquired drug resistance. Structural modeling indicated that a novel class of variants acts allosterically to destabilize the autoinhibited conformation of the ABL kinase, to which STI571 preferentially binds. The authors concluded that this screening strategy is a paradigm applicable to a growing list of target-directed anticancer agents and provides a means of anticipating the drug-resistant amino acid substitutions that are likely to be clinically problematic.
Resistance to tyrosine kinase inhibitors (TKIs) develops in virtually all cases of Philadelphia chromosome-positive acute lymphoblastic leukemia. Duy et al. (2011) reported the discovery of a novel mechanism of drug resistance that is based on protective feedback signaling of leukemia cells in response to treatment with TKIs. In Philadelphia chromosome-positive acute lymphoblastic leukemia cells, Duy et al. (2011) identified BCL6 (109565) as a central component of this drug-resistance pathway and demonstrated that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukemia-initiating subclones.
To determine whether the P210(bcr/abl) hybrid protein can induce leukemia, Daley et al. (1990) infected murine bone marrow with a retrovirus encoding this protein and transplanted the bone marrow into irradiated syngeneic recipients. Transplant recipients developed several hematologic malignancies, prominent among which was a myeloproliferative syndrome closely resembling the chronic phase of human chronic myelogenous leukemia. Tumor tissue from diseased mice harbored the provirus encoding P210(bcr/abl). Heisterkamp et al. (1990) satisfied Koch postulates in relation to leukemia by demonstrating leukemia in mice transgenic for a bcr/abl p190 construct of the type found in acute lymphoblastic leukemia. Tkachuk et al. (1990) used 2-color fluorescence in situ hybridization (FISH) with probes from portions of the BCR and ABL (189980) genes to detect the BCR-ABL fusion in individual blood and bone marrow cells from 6 patients. The fusion event was detected in all samples analyzed, of which 3 were cytogenetically Ph(1)-negative. One of the Ph(1)-negative samples was also PCR-negative.
When the Philadelphia-chromosome-positive chronic myeloid leukemia-blast crisis cell line BV173 is injected into SCID mice, a disease process closely resembling that seen in leukemia patients results (Kamel-Reid et al., 1989). For example, BCR-ABL transcripts are detectable in bone marrow, spleen, peripheral blood, liver, and lungs. Skorski et al. (1994) found that systemic treatment of the leukemic mice with a 26-mer BCR-ABL antisense oligodeoxynucleotide induced disappearance of leukemic cells and a marked decrease in BCR-ABL mRNA in mouse tissues. Untreated mice or mice treated with a BCR-ABL sense oligodeoxynucleotide or a 6-base-mismatched antisense oligodeoxynucleotide were dead 8 to 13 weeks after leukemia cell injection; in marked contrast, mice treated with BCR-ABL antisense oligodeoxynucleotide died of leukemia 18 to 23 weeks after injection of leukemic cells. Findings were interpreted as indicating the in vivo effectiveness of an anticancer therapy based on antisense oligodeoxynucleotides targeting a tumor-specific gene.
Cancer is thought to arise from multiple genetic events that establish irreversible malignancy. A different mechanism might be present in certain leukemias initiated by a chromosomal translocation. Huettner et al. (2000) adopted a new approach to determine if ablation of the genetic abnormality is sufficient for reversion. They generated a conditional transgenic model of BCR-ABL-induced leukemia. The most common form of the product of the fusion gene, p210 BCR-ABL1, is found in more than 90% of patients with chronic myelogenous leukemia and in up to 15% of adult patients with de novo acute lymphoblastic leukemia. Efforts to establish a useful transgenic model had been hampered by embryonic lethality when the oncogene is expressed during embryogenesis, by reduced penetrance, or by extremely long latency. Huettner et al. (2000) used the 'knock-in' approach to induce leukemia by p190 BCR-ABL1 (Castellanos et al., 1997). Lethal leukemia developed within an acceptable time frame in all animals, and complete remission was achieved by suppression of BCR-ABL1 expression, even after multiple rounds of induction and reversion. The results demonstrated that BCR-ABL1 is required for both induction and maintenance of leukemia. The findings suggested that complete and lasting remissions can be achieved if the genetic abnormality is abolished or silenced before secondary mutations are acquired. The results have implications for therapies that directly target leukemia oncogenes, with a relevant example being the use of BCR-ABL1-specific tyrosine kinase inhibitors.
Tanabe et al. (2000) designed a ribozyme which exclusively targets the junction sequence of BCR-ABL and showed that it specifically cleaves the BCR-ABL mRNA, inducing apoptosis in CML cells. Tanabe et al. (2000) tested this technology in vivo by embedding genes encoding the maxizyme downstream of genes for the human tRNA. They used a retroviral system for the expression of the maxizyme in leukemic cells. A line of CML cells was transduced either with a control vector in which the maxizyme sequence had been deleted or with the maxizyme-encoding vector. They then injected 2 x 10(6) transduced cells into the tail veins of NOD-SCID mice. Animals transduced with the control vector died between 6 and 13 weeks afterwards due to diffuse leukemia. Animals treated with the BCR-ABL ribozyme all survived, with no evidence of leukemia in 8 animals 8 weeks after inoculation. Tanabe et al. (2000) stated that their maxizyme could be useful for purging bone marrow in cases of CML treated by autologous transplantation, when it would presumably reduce the incidence of relapse by decreasing the tumorigenicity of contaminating CML cells in the transplant.
Voncken et al. (1995) found that exposure of Bcr-null mice to gram-negative endotoxin led to severe septic shock and increased tissue injury by neutrophils. Neutrophils of Bcr-null mice showed a pronounced increase in reactive oxygen metabolite production upon activation and were more sensitive to priming stimuli. Activated Bcr-null neutrophils displayed a 3-fold increase in Rac2 (602049) membrane translocation compared with wildtype neutrophils. The results showed that BCR is involved in the regulation of RAC-mediated superoxide production by the NADPH-oxidase system (see NOX1; 300225) of leukocytes and suggested a link between BCR function and the cell type affected in Philadelphia chromosome-positive leukemias.
Azam, M., Latek, R. R., Daley, G. Q. Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell 112: 831-843, 2003. [PubMed: 12654249] [Full Text: https://doi.org/10.1016/s0092-8674(03)00190-9]
Barbany, G., Hoglund, M., Simonsson, B. Complete molecular remission in chronic myelogenous leukemia after imatinib therapy. (Letter) New Eng. J. Med. 347: 539-540, 2002. [PubMed: 12181416] [Full Text: https://doi.org/10.1056/NEJM200208153470719]
Baxter, E. J., Hochhaus, A., Bolufer, P., Reiter, A., Fernandez, J. M., Senent, L., Cervera, J., Moscardo, F., Sanz, M. A., Cross, N. C. P. The t(4;22)(q12;q11) in atypical chronic myeloid leukaemia fuses BCR to PDGFRA. Hum. Molec. Genet. 11: 1391-1397, 2002. [PubMed: 12023981] [Full Text: https://doi.org/10.1093/hmg/11.12.1391]
Brunning, R. D. Philadelphia chromosome positive leukemia. Hum. Path. 11: 307-309, 1980. [PubMed: 6997180] [Full Text: https://doi.org/10.1016/s0046-8177(80)80024-4]
Budarf, M., Canaani, E., Emanuel, B. S. Linear order of the four BCR-related loci in 22q11. Genomics 3: 168-171, 1988. [PubMed: 3267213] [Full Text: https://doi.org/10.1016/0888-7543(88)90149-8]
Castellanos, A., Pintado, B., Weruaga, E., Arevalo, R., Lopez, A., Orfao, A., Sanchez-Garcia, I. A BCR-ABL(p190) fusion gene made by homologous recombination causes B-cell acute lymphoblastic leukemias in chimeric mice with independence of the endogenous bcr product. Blood 90: 2168-2174, 1997. [PubMed: 9310467]
Chissoe, S. L., Bodenteich, A., Wang, Y.-F., Wang, Y.-P., Burian, D., Clifton, S. W., Crabtree, J., Freeman, A., Iyer, K., Jian, L., Ma, Y., McLaury, H.-J., Pan, H.-Q., Sarhan, O. H., Toth, S., Wang, Z., Zhang, G., Heisterkamp, N., Groffen, J., Roe, B. A. Sequence and analysis of the human ABL gene, the BCR gene, and regions involved in the Philadelphia chromosomal translocation. Genomics 27: 67-82, 1995. [PubMed: 7665185] [Full Text: https://doi.org/10.1006/geno.1995.1008]
Croce, C. M., Huebner, K., Isobe, M., Fainstain, E., Lifshitz, B., Shtivelman, E., Canaani, E. Mapping of four distinct BCR-related loci to chromosome region 22q11: order of BCR loci relative to chronic myelogenous leukemia and acute lymphoblastic leukemia breakpoints. Proc. Nat. Acad. Sci. 84: 7174-7178, 1987. [PubMed: 3118359] [Full Text: https://doi.org/10.1073/pnas.84.20.7174]
Daley, G. Q., Van Etten, R. A., Baltimore, D. Induction of chronic myelogenous leukemia in mice by the P210(bcr/abl) gene of the Philadelphia chromosome. Science 247: 824-830, 1990. [PubMed: 2406902] [Full Text: https://doi.org/10.1126/science.2406902]
de Klein, A., Geurts van Kessel, A., Grosveld, G., Bartram, C. R., Hagemeijer, A., Bootsma, D., Spurr, N. K., Heisterkamp, N., Groffen, J., Stephenson, J. R. A cellular oncogene is translocated to the Philadelphia chromosome in chronic myelocytic leukaemia. Nature 300: 765-767, 1982. [PubMed: 6960256] [Full Text: https://doi.org/10.1038/300765a0]
Demiroglu, A., Steer, E. J., Heath, C., Taylor, K., Bentley, M., Allen, S. L., Koduru, P., Brody, J. P., Hawson, G., Rodwell, R., Doody, M.-L., Carnicero, F., Reiter, A., Goldman, J. M., Melo, J. V., Cross, N. C. P. The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: transforming activity and specific inhibition of FGFR1 fusion proteins. Blood 98: 3778-3783, 2001. [PubMed: 11739186] [Full Text: https://doi.org/10.1182/blood.v98.13.3778]
Diekmann, D., Brill, S., Garrett, M. D., Totty, N., Hsuan, J., Monfries, C., Hall, C., Lim, L., Hall, A. Bcr encodes a GTPase-activating protein for p21(rac). Nature 351: 400-402, 1991. [PubMed: 1903516] [Full Text: https://doi.org/10.1038/351400a0]
Dierks, C., Beigi, R., Guo, G.-R., Zirlik, K., Stegert, M. R., Manley, P., Trussell, C., Schmitt-Graeff, A., Landwerlin, K., Veelken, H., Warmuth, M. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on hedgehog pathway activation. Cancer Cell 14: 238-249, 2008. [PubMed: 18772113] [Full Text: https://doi.org/10.1016/j.ccr.2008.08.003]
Druker, B. J., Sawyers, C. L., Kantarjian, H., Resta, D. J., Reese, S. F., Ford, J. M., Capdeville, R., Talpaz, M. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. New Eng. J. Med. 344: 1038-1042, 2001. Note: Erratum: New Eng. J. Med. 345: 232 only, 2001. [PubMed: 11287973] [Full Text: https://doi.org/10.1056/NEJM200104053441402]
Druker, B. J., Talpaz, M., Resta, D. J., Peng, B., Buchdunger, E., Ford, J. M., Lydon, N. B., Kantarjian, H., Capdeville, R., Ohno-Jones, S., Sawyers, C. L. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. New Eng. J. Med. 344: 1031-1037, 2001. [PubMed: 11287972] [Full Text: https://doi.org/10.1056/NEJM200104053441401]
Duy, C., Hurtz, C., Shojaee, S., Cerchietti, L., Geng, H., Swaminathan, S., Klemm, L., Kweon, S., Nahar, R., Braig, M., Park, E., Kim, Y., and 11 others. BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition. Nature 473: 384-388, 2011. [PubMed: 21593872] [Full Text: https://doi.org/10.1038/nature09883]
Emanuel, B. S., Selden, J. R., Wang, E., Nowell, P. C., Croce, C. M. In situ hybridization and translocation breakpoint mapping. I. Non-identical 22q11 breakpoints for the t(9;22) of CML and the t(8;22) of Burkitt lymphoma. Cytogenet. Cell Genet. 38: 127-131, 1984. [PubMed: 6467987] [Full Text: https://doi.org/10.1159/000132044]
Erikson, J., Griffin, C., ar-Rushdi, A., Valtieri, M., Hoxie, J., Finan, J., Emanuel, B. S., Rovera, G., Nowell, P. C., Croce, C. M. Heterogeneity of chromosome 22 breakpoint in Philadelphia-positive (Ph+) acute lymphocytic leukemia. Proc. Nat. Acad. Sci. 83: 1807-1811, 1986. [PubMed: 3513189] [Full Text: https://doi.org/10.1073/pnas.83.6.1807]
Feinberg, A. P. Genomic imprinting and gene activation in cancer. Nature Genet. 4: 110-113, 1993. [PubMed: 8348145] [Full Text: https://doi.org/10.1038/ng0693-110]
Fioretos, T., Heisterkamp, N., Groffen, J. No evidence for genomic imprinting of the human BCR gene. Blood 83: 3441-3444, 1994. [PubMed: 8204871]
Fire, A. RNA-triggered gene silencing. Trends Genet. 15: 358-363, 1999. [PubMed: 10461204] [Full Text: https://doi.org/10.1016/s0168-9525(99)01818-1]
Fitzgerald, P. H. Evidence that chromosome band 22q12 is concerned with cell proliferation in chronic myeloid leukemia. Hum. Genet. 33: 269-274, 1976. [PubMed: 1067222] [Full Text: https://doi.org/10.1007/BF00286851]
Ganesan, T. S., Rassool, F., Guo, A.-P., Th'ng, K. H., Dowding, C., Hibbin, J. A., Young, B. D., White, H., Kumaran, T. O., Galton, D. A. G., Goldman, J. M. Rearrangement of the bcr gene in Philadelphia chromosome-negative chronic myeloid leukemia. Blood 68: 957-960, 1986. [PubMed: 2875753]
Goldman, J. M., Melo, J. V. Targeting the BCR-ABL tyrosine kinase in chronic myeloid leukemia. (Editorial) New Eng. J. Med. 344: 1084-1086, 2001. [PubMed: 11287980] [Full Text: https://doi.org/10.1056/NEJM200104053441409]
Goldman, J. M., Melo, J. V. Chronic myeloid leukemia--advances in biology and new approaches to treatment. New Eng. J. Med. 349: 1451-1464, 2003. [PubMed: 14534339] [Full Text: https://doi.org/10.1056/NEJMra020777]
Gorre, M. E., Mohammed, M., Ellwood, K., Hsu, N., Paquette, R., Rao, P. N., Sawyers, C. L. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293: 876-883, 2001. [PubMed: 11423618] [Full Text: https://doi.org/10.1126/science.1062538]
Griffin, C. A., McKeon, C., Israel, M. A., Gegonne, A., Ghysdael, J., Stehelin, D., Douglass, E. C., Green, A. A., Emanuel, B. S. Comparison of constitutional and tumor-associated 11;22 translocations: nonidentical breakpoints on chromosomes 11 and 22. Proc. Nat. Acad. Sci. 83: 6122-6126, 1986. [PubMed: 3461479] [Full Text: https://doi.org/10.1073/pnas.83.16.6122]
Groffen, J., Stephenson, J. R., Heisterkamp, N., de Klein, A., Bartram, C. R., Grosveld, G. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell 36: 93-99, 1984. [PubMed: 6319012] [Full Text: https://doi.org/10.1016/0092-8674(84)90077-1]
Grosveld, G., Verwoerd, T., van Agthoven, T., de Klein, A., Ramachandran, K. L., Heisterkamp, N., Stam, K., Groffen, J. The chronic myelocytic cell line K562 contains a breakpoint in bcr and produces a chimeric bcr/c-abl transcript. Molec. Cell. Biol. 6: 607-616, 1986. [PubMed: 3023859] [Full Text: https://doi.org/10.1128/mcb.6.2.607-616.1986]
Haas, O. A., Argyriou-Tirita, A., Lion, T. Parental origin of chromosomes involved in the translocation t(9;22). Nature 359: 414-416, 1992. [PubMed: 1406953] [Full Text: https://doi.org/10.1038/359414a0]
Haas, O. A. Are ABL and BCR imprinted? No definitive answers, but more questions. Leukemia 9: 740-745, 1995. [PubMed: 7723413]
Hariharan, I. K., Adams, J. M. cDNA sequence for human bcr, the gene that translocates to the abl oncogene in chronic myeloid leukaemia. EMBO J. 6: 115-119, 1987. [PubMed: 3107980] [Full Text: https://doi.org/10.1002/j.1460-2075.1987.tb04727.x]
Heisterkamp, N., Jenster, G., ten Hoeve, J., Zovich, D., Pattengale, P. K., Groffen, J. Acute leukaemia in bcr/abl transgenic mice. Nature 344: 251-253, 1990. [PubMed: 2179728] [Full Text: https://doi.org/10.1038/344251a0]
Heisterkamp, N., Stam, K., Groffen, J., de Klein, A., Grosveld, G. Structural organization of the bcr gene and its role in the Ph-1 translocation. Nature 315: 758-761, 1985. [PubMed: 2989703] [Full Text: https://doi.org/10.1038/315758a0]
Hermans, A., Heisterkamp, N., von Lindern, M., van Baal, S., Meijer, D., van der Plas, D., Wiedemann, L. M., Groffen, J., Bootsma, D., Grosveld, G. Unique fusion of bcr and c-abl genes in Philadelphia chromosome positive acute lymphoblastic leukemia. Cell 51: 33-40, 1987. [PubMed: 2820585] [Full Text: https://doi.org/10.1016/0092-8674(87)90007-9]
Huettner, C. S., Zhang, P., Van Etten, R. A., Tenen, D. G. Reversibility of acute B-cell leukaemia induced by BCR-ABL1. Nature Genet. 24: 57-60, 2000. [PubMed: 10615128] [Full Text: https://doi.org/10.1038/71691]
Justice, M. J., Siracusa, L. D., Gilbert, D. J., Heisterkamp, N., Groffen, J., Chada, K., Silan, C. M., Copeland, N. G., Jenkins, N. A. A genetic linkage map of mouse chromosome 10: localization of eighteen molecular markers using a single interspecific backcross. Genetics 125: 855-866, 1990. [PubMed: 1975791] [Full Text: https://doi.org/10.1093/genetics/125.4.855]
Kamel-Reid, S., Letarte, M., Sirard, C., Doedens, M., Grunberger, T., Fulop, G., Freedman, M. H., Phillips, R. A., Dick, J. E. A model of human acute lymphoblastic leukemia in immune-deficient SCID mice. Science 246: 1597-600, 1989. [PubMed: 2595371] [Full Text: https://doi.org/10.1126/science.2595371]
Klein, G. Specific chromosomal translocations and the genesis of the B-cell-derived tumors in mice and men. Cell 32: 311-315, 1983. [PubMed: 6402307] [Full Text: https://doi.org/10.1016/0092-8674(83)90449-x]
Koeffler, H. P., Golde, D. W. Chronic myelogenous leukemia--new concepts. New Eng. J. Med. 304: 1201-1209 and 1269-1274, 1981. [PubMed: 7012623] [Full Text: https://doi.org/10.1056/NEJM198105143042004]
Kohno, S.-I., Sandberg, A. A. Chromosomes and causation of human cancer and leukemia. XXXIX. Usual and unusual findings in Ph(1)-positive CML. Cancer 46: 2227-2237, 1980. [PubMed: 6932994] [Full Text: https://doi.org/10.1002/1097-0142(19801115)46:10<2227::aid-cncr2820461020>3.0.co;2-g]
Laurent, E., Talpaz, M., Kantarjian, H., Kurzrock, R. The BCR gene and Philadelphia chromosome-positive leukemogenesis. Cancer Res. 61: 2343-2355, 2001. [PubMed: 11289094]
Lillicrap, D. A., Sterndale, H. Familial chronic myeloid leukaemia. (Letter) Lancet 324: 699 only, 1984. Note: Originally Volume II. [PubMed: 6147726] [Full Text: https://doi.org/10.1016/s0140-6736(84)91260-1]
Lim, Y.-M., Wong, S., Lau, G., Witte, O. N., Colicelli, J. BCR/ABL inhibition by an escort/phosphatase fusion protein. Proc. Nat. Acad. Sci. 97: 12233-12238, 2000. [PubMed: 11027300] [Full Text: https://doi.org/10.1073/pnas.210253497]
Litz, C. E., Copenhaver, C. M. Paternal origin of the rearranged major breakpoint cluster region in chronic myeloid leukemia. Blood 83: 3445-3448, 1994. [PubMed: 8204872]
Maru, Y., Witte, O. N. The BCR gene encodes a novel serine/threonine kinase activity within a single exon. Cell 67: 459-468, 1991. [PubMed: 1657398] [Full Text: https://doi.org/10.1016/0092-8674(91)90521-y]
Melo, J. V., Yan, X.-H., Diamond, J., Goldman, J. M. Lack of imprinting of the ABL gene. (Letter) Nature Genet. 8: 318-319, 1994. [PubMed: 7894478] [Full Text: https://doi.org/10.1038/ng1294-318]
Melo, J. V., Yan, X.-H., Diamond, J., Goldman, J. M. Balanced parental contribution to the ABL component of the BCR-ABL gene in chronic myeloid leukemia. Leukemia 9: 734-745, 1995. [PubMed: 7723412]
Mes-Masson, A.-M., McLaughlin, J., Daley, G. Q., Paskind, M., Witte, O. N. Overlapping cDNA clones define the complete coding region for the P210(c-abl) gene product associated with chronic myelogeneous leukemia cells containing the Philadelphia chromosome. Proc. Nat. Acad. Sci. 83: 9768-9772, 1986. Note: Erratum: Proc. Nat. Acad. Sci. 84: 2507 only, 1987. [PubMed: 3540951] [Full Text: https://doi.org/10.1073/pnas.83.24.9768]
Mitelman, F., Levan, G. Clustering of aberrations to specific chromosomes in human neoplasms. III. Incidence and geographic distribution of chromosome aberrations in 856 cases. Hereditas 89: 207-232, 1978. [PubMed: 730541] [Full Text: https://doi.org/10.1111/j.1601-5223.1978.tb01277.x]
Mullighan, C. G., Miller, C. B., Radtke, I., Phillips, L. A., Dalton, J., Ma, J., White, D., Hughes, T. P., Le Beau, M. M., Pui, C.-H., Relling, M. V., Shurtleff, S. A., Downing, J. R. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature 453: 110-114, 2008. [PubMed: 18408710] [Full Text: https://doi.org/10.1038/nature06866]
Notta, F., Mullighan, C. G., Wang, J. C. Y., Poeppl, A., Doulatov, S., Phillips, L. A., Ma, J., Minden, M. D., Downing, J. R., Dick, J. E. Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. Nature 469: 362-367, 2011. Note: Erratum: Nature 471: 254 only, 2011. [PubMed: 21248843] [Full Text: https://doi.org/10.1038/nature09733]
Nowell, P. C., Hungerford, D. A. A minute chromosome in human chronic granulocytic leukemia. (Abstract) Science 132: 1497, 1960.
Nowell, P. C., Hungerford, D. A. Chromosome studies on normal and leukemic human leukocytes. J. Nat. Cancer Inst. 25: 85-109, 1960. [PubMed: 14427847]
Olavarria, E., Craddock, C., Dazzi, F., Marin, D., Marktel, S., Apperley, J. F., Goldman, J. M. Imatinib mesylate (STI571) in the treatment of relapse of chronic myeloid leukemia after allogeneic stem cell transplantation. Blood 99: 3861-3862, 2002. [PubMed: 11986250] [Full Text: https://doi.org/10.1182/blood.v99.10.3861]
Pegoraro, L., Matera, L., Ritz, J., Levis, A., Palumbo, A., Biagini, G. Establishment of a Ph(1)-positive human cell line (BV173). J. Nat. Cancer Inst. 70: 447-451, 1983. [PubMed: 6572735]
Perrotti, D., Cesi, V., Trotta, R., Guerzoni, C., Santilli, G., Campbell, K., Iervolino, A., Condorelli, F., Gambacorti-Passerini, C., Caligiuri, M. A., Calabretta, B. BCR-ABL suppresses C/EBP-alpha expression through inhibitory action of hnRNP E2. Nature Genet. 30: 48-58, 2002. [PubMed: 11753385] [Full Text: https://doi.org/10.1038/ng791]
Prakash, O., Yunis, J. J. High resolution chromosomes of the t(9;22) positive leukemias. Cancer Genet. Cytogenet. 11: 361-367, 1984. [PubMed: 6584200] [Full Text: https://doi.org/10.1016/0165-4608(84)90015-3]
Priest, J. R., Robison, L. L., McKenna, R. W., Lindquist, L. L., Warkentin, P. I., LeBien, T. W., Woods, W. G., Kersey, J. H., Coccia, P. F., Nesbit, M. E., Jr. Philadelphia chromosome positive childhood acute lymphoblastic leukemia. Blood 56: 15-22, 1980. [PubMed: 6930307]
Rowley, J. D. A new consistent chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine fluorescence and Giemsa staining. Nature 243: 290-293, 1973. [PubMed: 4126434] [Full Text: https://doi.org/10.1038/243290a0]
Rubin, C. M., Carrino, J. J., Dickler, M. N., Leibowitz, D., Smith, S. D., Westbrook, C. A. Heterogeneity of genomic fusion of BCR and ABL in Philadelphia chromosome-positive acute lymphoblastic leukemia. Proc. Nat. Acad. Sci. 85: 2795-2799, 1988. [PubMed: 2833755] [Full Text: https://doi.org/10.1073/pnas.85.8.2795]
Saglio, G., Storlazzi, C. T., Giugliano, E., Surace, C., Anelli, L., Rege-Cambrin, G., Zagaria, A., Velasco, A. J., Heiniger, A., Scaravaglio, P., Gomez, A. T., Gomez, J. R., Archidiacono, N., Banfi, S., Rocchi, M. A 76-kb duplicon maps close to the BCR gene on chromosome 22 and the ABL gene on chromosome 9: possible involvement in the genesis of the Philadelphia chromosome translocation. Proc. Nat. Acad. Sci. 99: 9882-9887, 2002. [PubMed: 12114534] [Full Text: https://doi.org/10.1073/pnas.152171299]
Savage, D. G., Antman, K. H. Imatinib mesylate--a new oral targeted therapy. New Eng. J. Med. 346: 683-693, 2002. [PubMed: 11870247] [Full Text: https://doi.org/10.1056/NEJMra013339]
Scherr, M., Battmer, K., Winkler, T., Heidenreich, O., Ganser, A., Eder, M. Specific inhibition of bcr-abl gene expression by small interfering RNA. Blood 101: 1566-1569, 2003. [PubMed: 12393533] [Full Text: https://doi.org/10.1182/blood-2002-06-1685]
Shtivelman, E., Gale, R. P., Dreazen, O., Berrebi, A., Zaizov, R., Kubonishi, I., Miyoshi, I., Canaani, E. bcr-abl RNA in patients with chronic myelogenous leukemia. Blood 69: 971-973, 1987. [PubMed: 3101769]
Shtivelman, E., Lifshitz, B., Gale, R. P., Canaani, E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature 315: 550-554, 1985. [PubMed: 2989692] [Full Text: https://doi.org/10.1038/315550a0]
Skorski, T., Nieborowska-Skorska, M., Nicolaides, N. C., Szczylik, C., Iversen, P., Iozzo, R. V., Zon, G., Calabretta, B. Suppression of Philadelphia-1 leukemia cell growth in mice by BCR-ABL antisense oligodeoxynucleotide. Proc. Nat. Acad. Sci. 91: 4504-4508, 1994. [PubMed: 8183938] [Full Text: https://doi.org/10.1073/pnas.91.10.4504]
Stam, K., Heisterkamp, N., Grosveld, G., de Klein, A., Verma, R. S., Coleman, M., Dosik, H., Groffen, J. Evidence of a new chimeric bcr/c-abl mRNA in patients with chronic myelocytic leukemia and the Philadelphia chromosome. New Eng. J. Med. 313: 1429-1433, 1985. [PubMed: 3864009] [Full Text: https://doi.org/10.1056/NEJM198512053132301]
Stam, K., Heisterkamp, N., Reynolds, F. H., Jr., Groffen, J. Evidence that the phl gene encodes a 160,000-dalton phosphoprotein with associated kinase activity. Molec. Cell. Biol. 7: 1955-1960, 1987. [PubMed: 3299055] [Full Text: https://doi.org/10.1128/mcb.7.5.1955-1960.1987]
Swan, D. C., McBride, O. W., Robbins, K. C., Keithley, D. A., Reddy, E. P., Aaronson, S. A. Chromosomal mapping of the simian sarcoma virus onc gene analogue in human cells. Proc. Nat. Acad. Sci. 79: 4691-4695, 1982. [PubMed: 6289313] [Full Text: https://doi.org/10.1073/pnas.79.15.4691]
Tanabe, T., Kuwabara, T., Warashina, M., Tani, K., Taira, K., Asano, S. Oncogene inactivation in a mouse model: tissue invasion by leukaemic cells is stalled by loading them with a designer ribozyme. Nature 406: 473-474, 2000. [PubMed: 10952298] [Full Text: https://doi.org/10.1038/35020190]
Teyssier, J. R., Bartram, C. R., Deville, J., Potron, G., Pigeon, F. C-abl oncogene and chromosome 22 'bcr' juxtaposition in chronic myelogenous leukemia. New Eng. J. Med. 312: 1393-1394, 1985. [PubMed: 3857461] [Full Text: https://doi.org/10.1056/NEJM198505233122118]
Tkachuk, D. C., Westbrook, C. A., Andreeff, M., Donlon, T. A., Cleary, M. L., Suryanarayan, K., Homge, M., Redner, A., Gray, J., Pinkel, D. Detection of bcr-abl fusion in chronic myelogeneous leukemia by in situ hybridization. Science 250: 559-562, 1990. [PubMed: 2237408] [Full Text: https://doi.org/10.1126/science.2237408]
Verhest, A., Monsieur, R. Philadelphia chromosome-positive thrombocythemia with leukemic transformation. (Letter) New Eng. J. Med. 308: 1603, 1983. [PubMed: 6574316] [Full Text: https://doi.org/10.1056/NEJM198306303082620]
Verma, R. S., Dosik, H. Heteromorphisms of the Philadelphia (Ph-1) chromosome in patients with chronic myelogenous leukaemia (CML). I. Classification and clinical significance. Brit. J. Haemat. 45: 215-222, 1980. [PubMed: 6934005] [Full Text: https://doi.org/10.1111/j.1365-2141.1980.tb07141.x]
Voncken, J. W., van Schaick, H., Kaartinen, V., Deemer, K., Coates, T., Landing, B., Pattengale, P., Dorseuil, O., Bokoch, G. M., Groffen, J., Heisterkamp, N. Increased neutrophil respiratory burst in bcr-null mutants. Cell 80: 719-728, 1995. [PubMed: 7889565] [Full Text: https://doi.org/10.1016/0092-8674(95)90350-x]
Zhao, C., Chen, A., Jamieson, C. H., Fereshteh, M., Abrahamsson, A., Blum, J., Kwon, H. Y., Kim, J., Chute, J. P., Rizzieri, D., Munchhof, M., VanArsdale, T., Beachy, P. A., Reya, T. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458: 776-779, 2009. Note: Erratum: Nature 460: 652 only, 2009. [PubMed: 19169242] [Full Text: https://doi.org/10.1038/nature07737]