BCR
Primary Author(s)*
Brian Davis, PhD
Synonyms
BCR, RhoGEF and GTPase activating protein; Breakpoint Cluster Region; BCR1; ALL; CML; PHL; D22S11; D22S662
Genomic Location
Cytoband: 22q11.23
Genomic Coordinates:
GRCh38.p12 23180365..23318037
Cancer Category/Type
Chronic Myeloid Leukemia (also referred as (Chronic Myelogenous Leukemia)
More than 90% of patients diagnosed with Chronic Myeloid Leukemia bear a Philadelphia chromosome resulting from t(9;22)(q34.1;q11.2), which is a reciprocal translocation between chromosome 22 (BCR locus) and chromosome 9 (ABL1 locus) (see OMIM) [1]. The Drug Imatinib mesylate, also known as Gleevec, was the one of the first molecularly developed drugs, and has a remarkably high success rate in treatment of patients with Chronic Myeloid Leukemia by targeting the BCR/ABL1 fusion product [5].
Approximately 20% of patients (25 - 30% of adults and 2 - 10% of children) diagnosed with Acute Lymphoblastic Leukemia bear a Philadelphia chromosome resulting from t(9;22)(q34.1;q11.2), which is a reciprocal translocation between chromosome 22 (BCR locus) and chromosome 9 (ABL1 locus) (see OMIM) [1]. Treatment of Acute Lymphoblastic Leukemia patients with Gleevec does not have the same success as in Chronic Myeloid Leukemia patients because the genomic instability of ALL cells contributes to point mutations arising in the BRC-ABL1 kinase domain, leading to Gleevec resistance [4].
Gene Overview
The function of the normal BCR gene product is as a GTPase-activating protein for RAC1 and CDC42. BCR promotes the exchange of RAC or CDC42-bound GDP by GTP, thereby activating them. The protein has serine/threonine kinase activity [9]. By far the most prevalent BCR alteration associated with cancer are the fusions of the ABL1 gene with a number of partners, but especially with the BCR gene in CML [1,2] and to a lesser extent in B-ALL and T-ALL.
The head to tail arrangement of the BCR-ABL1 fusion gene results in an activated tyrosine kinase activity [6]. It appears that the N-terminal domain of BCR can cause oligomerization of the BCR-ABL1 protein product, thus activating the ABL1 tyrosine kinase domain of the fusion protein [6,10,11].
See the "ABL1 gene" for additional details of the BCR-ABL1 gene fusion.
Common Alteration Types
By far the most common BCR alteration associated with cancer is the BCR-ABL1 fusion as described above in CML and ALL.
A small number of individual patients have been described with a BCR-JAK2 (Janus Kinase 2) fusion gene leading to CML and other hematological neoplasms, but this fusion gene appears to be rare (see [1] Atlas of Genetics and Cytogenetics in Oncology and Haematology]) [12,13,14].
A small number of chronic myeloproliferative disorders patients have been described with BCR-FGFR1 and BCR-PDGFRA fusion genes [15].
Somatic mutations of BCR have rarely been found spread throughout the gene (see COSMIC June 2018, indicating these are probably mostly carrier mutations. The exception may be the point mutation D1106N in the RhoGAP domain which occurs more frequently and has been associated with Colon Cancer.
| Copy Number Loss | Copy Number Gain | LOH | Loss-of-Function Mutation | Gain-of-Function Mutation | Translocation/Fusion |
|---|---|---|---|---|---|
| X | X |
Internal Pages
See the "ABL1 gene" for additional details of the BCR-ABL1 gene fusion.
External Links
BCR by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information
BCR by COSMIC - sequence information, expression, catalogue of mutations
BCR-ABL1 by CIViC - general knowledge and evidence-based variant specific information
BCR by St. Jude ProteinPaint mutational landscape and matched expression data.
BCR by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs
BCR by Cancer Index - gene, pathway, publication information matched to cancer type
BCR-ABL1 by OncoKB - mutational landscape, mutation effect, variant classification
BCR by My Cancer Genome - brief gene overview
BCR by UniProt - protein and molecular structure and function
BCR by Pfam - gene and protein structure and function information
BCR by GeneCards - general gene information and summaries
BCR by OMIM - compendium of human genes and genetic phenotypes
References
1. Drucker BJ, et al., (2001). 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. NEJM 344:1038-1042. PMID 11287973. DOI: 10.1056/NEJM200104053441402.
2. Faderl S, et al., (1999). The biology of chronic myeloid leukemia. NEJM 341:164-172, PMID 10403855. DOI: 10.1056/NEJM199907153410306.
3. Wong S and Witte ON, (2004). The BCR-ABL story: bench to bedside and back. Annu Rev Immunol 22:247-306, PMID 15032571. DOI: 10.1146/annurev.immunol.22.012703.104753.
4. Soverini S, et al., (2014). Drug resistance and BCR-ABL kinase domain mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia from the imatinib to the second-generation tyrosine kinase inhibitor era: The main changes are in the type of mutations, but not in the frequency of mutation involvement. Cancer 120:1002-1009, PMID 24382642. DOI: 10.1002/cncr.28522.
5. Drucker BJ, et al., (2001). Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. New England Journal of Medicine 344:1031–1037, PMID 11287972. DOI: 10.1056/NEJM200104053441401.
6. Greuber EK, et al., (2013). Role of ABL family kinases in cancer: from leukaemia to solid tumours. Nat Rev Cancer 13:559–571, PMID 23842646. DOIi: 10.1038/nrc3563.
7. Quintás-Cardama A and Cortes J, (2008). Therapeutic Options Against BCR-ABL1 T315I-Positive Chronic Myelogenous Leukemia. Clinical Cancer Research 14:4392-4399, PMID 18628453. DOI: 10.1158/1078-0432.CCR-08-0117.
8. Redaelli S, et al., (2009). Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol 27:469-471, PMID 19075254. DOI: 10.1200/JCO.2008.19.8853.
9. Diekmann D, et al., (1991). Bcr encodes a GTPase-activating protein for p21rac. Nature 35:400-402, PMID 1903516. DOI: 10.1038/351400a0.
10. McWhirter JR and Wang JY, (1991). Activation of tyrosinase kinase and microfilament-binding functions of c-abl by bcr sequences in bcr/abl fusion proteins. Mol Cell Biol 11:1553-1565, PMID 1705008.
11. Muller AJ, et al., (1991). BCR first exon sequences specifically activate the BCR/ABL tyrosine kinase oncogene of Philadelphia chromosome-positive human leukemias. Mol Cell Biol 11:1785-1792, PMID 2005881.
12. Griesinger F, et al., (2005). 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. Genes Chromosomes Cancer 44:329-333, PMID 16001431. DOI: 10.1002/gcc.20235.
13. He R., (2016). BCR-JAK2 fusion in a myeloproliferative neoplasm with associated eosinophilia. Cancer Genet 209:223-228, PMID: 27134074. DOI: 10.1016/j.cancergen.2016.03.002.
14. Jatiani SS, et al., (2010), JAK/STAT Pathways in Cytokine Signaling and Myeloproliferative Disorders: Approaches for Targeted Therapies. Genes Cancer 1(10):979-993, PMID 21442038. doi: 10.1177/1947601910397187.
15. Cross NCP and Reiter A, (2002). Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Leukemia 16:1207-1212, PMID 12094244. https://doi.org/10.1038/sj.leu.2402556.
Notes
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