BCR (Breakpoint cluster region)

2008-08-01   Ali G Turhan 

Pole de Biologie-Sante - 40 avenue du Recteur Pineau - 86022 Poitiers Cedex, France


Atlas Image
Atlas Image
BCR (Breakpoint cluster region) Hybridization with SureFISH BCR BA probe (Agilent Technologies, Australia) showing the BCR gene on 22q11.23 (red-green or a fused yellow signal) - Courtesy Adriana Zamecnikova.


Atlas Image
DNA Diagram


About 23 exons; 130 kb; 5 centromere - 3 telomere orientation.


Into various mRNA, of which are 4.5 kb and 7 kb.



130 KDa, 190 KDa; mainly 160 KDa (1271 amino acids); N-term ATP binding/Serine-Threonine kinase domain, SH2 binding, GTP/GDP exchange domain, and C-term domain which functions as a GTPase activating protein for p21rac.


Ubiquitously expressed, with highest expression in brain and hematopoietic tissue.




Protein (serine/threonine) kinase; includes major signalisation domains such as:
  • Oligomerization domain, responsible of homotetramerization of BCR-ABL molecule and necessary for its transforming potential;
  • Serine threonine kinase domain, including at least three SH2 binding sites; able to interact with proteins with SH2 domains: These sites include TYR177, necessary for binding of Grb2 and activation of RAS pathway and beta-isoform of 14-3-3 proteins;
  • GEF domain, in which lie the binding activity to the xeroderma pigmentosum protein, involved in DNA repair;
  • A COOH-terminal RAC-GAP domain which does not participate to hybrid BCR-ABL proteins.
    From the functional point of view, the role of bcr has been studies in bcr-null mice which shows an increased respiratory burst suggesting the involvement of bcr protein in the regulation of superoxide production , probably via RAC.
    In the context of CML, the role of bcr protein has been studies in in vitro and in vivo models; bcr gene has been shown to be a negative regulator of BCR-ABL. Its reduced expression increases the transforming potential of BCR-ABL. When overexpressed, bcr blocks BCR-ABL-mediated transformation in experimental mouse models. Serine 354 is required for the inhibitory function of bcr over BCR-ABL, as kinase mutants of bcr overexpressed in BCR-ABL expressing cells induce an increased tumorigenicity.
  • Homology

    Drosophila rotund protein; other guanine-nucleotide releasing factors of the CDC24 family.

    Implicated in

    All CML have a t(9;22), at least at the molecular level (BCR/ABL); phenotype and stem cell origin: multipotent progenitor: t(9;22) is found in all myeloid and B- lineage progenitors.
    The prognosis of CML has changed radically over the last 10 years, due to the development of novel drugs able to target the enhanced tyrosine kinase activity of BCR-ABL. The first of these therapies is Imatinib Mesylate (Gleevec) which has become the first line therapy for all patients with CML (See ABL and CML). In the first cohort trial of patients treated with Imatinib mesylate, the rates of complete cytogenetics responses (CCR) were exceptionally high (82 %) as compared to standard IFN-alpha - ARA-C therapy. At the most recent 6-year update, the overall survival is 90 % and most interestingly, the rates of progression towards more aggressive phases have been found to be progressively decreasing in all patients with major molecular responses (MMR). (For definition of MMR see CML). In IM-resistant or relapsing Ph1+ CML patients, second generation tyrosine kinase inhibitor (TKI) therapies such as Dasatinib (a dual SRC and ABL inhibitor) and Nilotinib have also recently become available.
    Anomalies additional to the t(9;22) may be found either at diagnosis or during course of the disease, or at the time of acute transformation; mainly: +der(22), +8, i(17q), +19; +21, -Y, -7, -17,+17; variant translocations: t(9;22;V) and apparent t(V;22) or t(9;V), where V is a variable chromosome, karyotypes with apparently normal chromosomes 9 and 22, may be found.
    Deletion of the derivative chromosome 9: Detected at diagnosis (in 10% of patients), probably indiacting a genetic instability phenotype, this finding has been associated to the more aggressive behavior of the disease, a poor prognostic factor potentially reversed by the use of imatinib mesylate.
    Hybrid gene
    see below
    Atlas Image
    72M14 on a case of CML with t(9/22). Note that the probe remains on der(22) (Ph) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics .
    Fusion protein
    see below
    see below
    Most often CD 10+ B-ALL; frequent CNS involvement.
    The prognosis of Ph1+ ALL has changed since the introduction of tyrosine-kinase inhibitor therapies, especially imatinib mesylate which is currently used as a first line therapy associated with either high dose chemotherapy or classical ALL-type induction (steroids+ vincristine) and maintenance. Allogeneic stem cell transplantation is indicated in Ph1+ ALL patients relapsing after Imatinib-based regimens. In IM-resistant or relapsing Ph1+ ALL patients, second generation tyrosine kinase inhibitor (TKI) therapies such as Dasatinib (a dual SRC and ABL inhibitor) and Nilotinib have also recently become available.
    The chromosome anomaly t(9;22) disappear during remission, in contrast with BC-CML cases (CML in blast crisis); additional anomalies: +der(22), -7, del(7q) most often, +8, but not an i(17q), in contrast with CML and AML cases; complex karyotypes, often hyperploid; variants and complex translocations may be found as in CML.
    Hybrid gene
    see below. In Both CML and Ph1+ ALL, detection and quantification of p210 BCR-ABL and p190 BCR-ABL have become the cornerstones of monitoring targeted therapies.
    Fusion protein
    see below
    see below
    AML mostly M1 or M2 AML
    High rates of hematologic , cytogenetic and molecular responses have been reported in de novo PH1+ AML, which is a rare entity.
    The chromosome anomaly t(9;22) disappear during remission, in contrast with BC-CML cases (CML in blast crisis); additional anomalies: similar to what is found in CML.
    Hybrid gene
    BCR/ABL the crucial event lies on der(22), id est 5 BCR - 3 ABL hybrid gene is the crucial one, while ABL/BCR may or may not be expressed;
    Breakpoint in ABL is variable over a region of 200 kb, often between the two alternative exons 1b and 1a, sometimes 5 of 1b or 3 of 1a, but always 5 of exon 2; breakpoint in BCR is either:
  • 1- in a region called M-bcr (for major breakpoint cluster region), a cluster of 5.8 kb, between exons 12 and 16, also called b1 to b5 of M-bcr; most breakpoints being either between b2 and b3, or between b3 and b4; transcript is 8.5 kb long; this results in a 210 KDa chimeric protein (P210); this is found in (most cases of) CML, and in half cases of ALL or AML.
  • 2- in a 35 kb region between exons 1 and 2, called m-bcr (minor breakpoint cluster region), -> 7 kb mRNA, resulting in a 190 KDa protein (P190) found in approximately 25% of adult ALL cases.
  • 3- A breakpoint in the exon 19 of BCR (designed as the micro-bcr) with fusion to abl sequences (a2) has been found in neutrophilic CML, with presence of a larger protein (P230).
  • Fusion protein
    BCR/ABL P210 comprises the first 902 or 927 amino acids from N-term of BCR, whereas P190 BCR and P230 include 427 and 1176 aminoacids respectively, from the N-term region of BCR; BCR/ABL has a cytoplasmic localization, probably by the ability of the oligomerization domain to interact with Factin. ABL is both nuclear and cytoplasmic, due to the presence of nuclear localisation and export signals (NLS and NES) within its COOH terminal region.
    All three forms of BCR-ABL oncogenes have transforming potential and it is now clear that they are responsible for initiation of the leukemic process associated with BCR-ABL oncogenes: Several signalling pathways are simultaneously activated and some phenotypic correlations can be made with the molecular abnormalities
  • 1- Constitutive activation of RAS pathway (via TYR177 of the BCR) mimicking the growth-factor-stimulation of cells, leads to a proliferative behavior;
  • 2- Activation of PI-3K/Akt as well as JAK/STAT pathways is most likely responsible for the anti-apoptotic potential;
  • 3- BCR/ABL provokes cell adhesive abnormalities (via CRK-L, FAK) as well as abnormalities of cell migration (via CXCR-4 whose expression is downregulated in CML cells expressing high levels of BCR-ABL). In experimental settings CD44 has been shown to play a major role in homing of BCR-ABL expressing cells. Activation of focal adhesion molecules (FAK / ) via CRK-L as well as abnormal response to SDF-1 leads to adhesive and migratory abnormalities of leukemic cells. It should be noted that specific signalling events leading to ALL with P190 and to CML with P210 have not been clearly established. A differential activation of Rho protein could play a role between the two phenotypes: rho Rac and cdc42 interact with BCR-ABL p210 but BCR-ABL p190 activates rac and cdc42 only. Deletion of Ikaros, has recently been implicated as a major oncogenic event cooperating with BCR-ABL in the BCR-ABL+ ALL.
  • Progression to blast crisis in CML: Multiple events could be involved, with the major phenotype being a genetic instability: 1-Mutation of P53, 2-methylation of internal ABL promoter; 3- telomere shortening; 4- Inhibition of negative regulators of BCR-ABL (such as Abi-1) 5- BCR-ABL induces a major genetic instability: Molecular pathways involved in this phenomenon have recently been elucidated (See ABL AND CML).
  • Breakpoints

    Atlas Image


    Pubmed IDLast YearTitleAuthors
    124763022002Bcr: a negative regulator of the Bcr-Abl oncoprotein in leukemia.Arlinghaus RB et al
    149828762004The biology of CML blast crisis.Calabretta B et al
    110716262000The molecular biology of chronic myeloid leukemia.Deininger MW et al
    112641752001BCR-ABL down-regulates the DNA repair protein DNA-PKcs.Deutsch E et al
    31079801987cDNA sequence for human bcr, the gene that translocates to the abl oncogene in chronic myeloid leukaemia.Hariharan IK et al
    145085242003Differential interaction and activation of Rho family GTPases by p210bcr-abl and p190bcr-abl.Harnois T et al
    28205851987Unique fusion of bcr and c-abl genes in Philadelphia chromosome positive acute lymphoblastic leukemia.Hermans A et al
    169984832006Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells.Krause DS et al
    112890942001The BCR gene and philadelphia chromosome-positive leukemogenesis.Laurent E et al
    184087102008BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros.Mullighan CG et al
    179345182008Kinase domain mutants of Bcr enhance Bcr-Abl oncogenic effects.Perazzona B et al
    117533852002BCR-ABL suppresses C/EBPalpha expression through inhibitory action of hnRNP E2.Perrotti D et al
    98747961999The BCR-ABL oncoprotein potentially interacts with the xeroderma pigmentosum group B protein.Takeda N et al
    78895651995Increased neutrophil respiratory burst in bcr-null mutants.Voncken JW et al
    104426321999Bcr: a negative regulator of the Bcr-Abl oncoprotein.Wu Y et al

    Other Information

    Locus ID:

    NCBI: 613
    MIM: 151410
    HGNC: 1014
    Ensembl: ENSG00000186716


    dbSNP: 613
    ClinVar: 613
    TCGA: ENSG00000186716


    Gene IDTranscript IDUniprot

    Expression (GTEx)



    PathwaySourceExternal ID
    Chronic myeloid leukemiaKEGGko05220
    Pathways in cancerKEGGhsa05200
    Chronic myeloid leukemiaKEGGhsa05220
    Diseases of signal transductionREACTOMER-HSA-5663202
    Signaling by FGFR in diseaseREACTOMER-HSA-1226099
    Signaling by FGFR1 in diseaseREACTOMER-HSA-5655302
    FGFR1 mutant receptor activationREACTOMER-HSA-1839124
    Signaling by cytosolic FGFR1 fusion mutantsREACTOMER-HSA-1839117
    Signal TransductionREACTOMER-HSA-162582
    Signaling by Rho GTPasesREACTOMER-HSA-194315
    Rho GTPase cycleREACTOMER-HSA-194840

    Protein levels (Protein atlas)

    Not detected


    Entity IDNameTypeEvidenceAssociationPKPDPMIDs
    PA166177510inotuzumab ozogamicinChemicalLabelAnnotationassociated
    PA445316Philadelphia ChromosomeDiseaseVipGeneassociated6960256, 2676087
    PA446171Leukemia, Myelogenous, Chronic, BCR-ABL PositiveDiseaseVipGeneassociated


    Pubmed IDYearTitleCitations
    188271852009Molecular biology of bcr-abl1-positive chronic myeloid leukemia.157
    185387332008Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression.155
    169984832006Requirement for CD44 in homing and engraftment of BCR-ABL-expressing leukemic stem cells.131
    221844102012Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival.129
    177102272007Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency.120
    168556312006Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate.92
    203517142011Poor replication of candidate genes for major depressive disorder using genome-wide association data.92
    190618392008Transient potent BCR-ABL inhibition is sufficient to commit chronic myeloid leukemia cells irreversibly to apoptosis.91
    251324972014BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia.87
    239741922013Independent prognostic value of BCR-ABL1-like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B-cell precursor ALL.84


    Ali G Turhan

    BCR (Breakpoint cluster region)

    Atlas Genet Cytogenet Oncol Haematol. 2008-08-01

    Online version: http://atlasgeneticsoncology.org/gene/55/bcrid55

    Historical Card

    2001-04-01 BCR (Breakpoint cluster region) by  Ali G Turhan 

    Pole de Biologie-Sante - 40 avenue du Recteur Pineau - 86022 Poitiers Cedex, France

    1997-10-01 BCR (Breakpoint cluster region) by  Jean-Loup Huret 

    Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France