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 t(9;22)(q34.1;q11.2), which is a reciprocal translocation between chromosome 22 (BCR locus) and chromosome 9 (ABL1 locus (1, also see OMIM). 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 (5)
Approximately 20% of patients (25 - 30% of adult and 2 - 10% of children) diagnosed with Acute Lymphoblastic Leukemia bear a Philadelphia chromosome t(9;22)(q34.1;q11.2), which is a reciprocal translocation between chromosome 22 (BCR locus) and chromosome 9 (ABL1 locus) (1, also see OMIM). Treatment of Acute Lymphoblastic Leukemia patients with Gleevec do not have the same success as Chronic Myeloid Leukemia patients treated with Gleevec, as the genomic instability of ALL cells contribute to point mutations arising in the BRC-ABL kinase domain, leading to resistance to Gleevec (4).
Gene Overview
The function of the normal BCR gene product is as a GTPase-activating protein for RAC1 and CDC42. 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 BCR gene with a number of parters, but especially with the ABL1 gene. A reciprocal translocation between chromosome 22 (BCR locus) and chromosome 9 (ABL1 locus) produces the Philadelphia chromosome t(9;22)(q34.1;q11.2), which is prevalent in Chronic Myeloid Leukemia (1, 2) and to a lesser extent in B-cell Acute Lymphoblastic Leukemia and T-cell Acute Lymphoblastic Leukemia. 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).
Common Alteration Types
BCR-ABL1
BCR-JAK2
BCR-FGFR1
BCR-PDCFRA
| Copy Number Loss | Copy Number Gain | LOH | Loss-of-Function Mutation | Gain-of-Function Mutation | Translocation/Fusion |
|---|---|---|---|---|---|
| EXAMPLE: X | EXAMPLE: X | EXAMPLE: X | EXAMPLE: X | EXAMPLE: X | EXAMPLE: X |
Internal Pages
Put your text here
External Links
Put your text here - Include as applicable links to: 1) Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2) COSMIC, 3) CIViC, 4) St. Jude ProteinPaint, 5) Precision Medicine Knnowledgebase (Weill Cornell), 6) Cancer Index, 7) OncoKB, 8) My Cancer Genome, 9) UniProt, 10) Pfam, 11) GeneCards, 12) GeneReviews, and 13) Any gene-specific databases.
EXAMPLES
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 120:1002-9, PMID 24382642 DOI: 10.1002/cncr.28522
5. Drucker, B. J., 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, E.K. 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: 4392-9. 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: 469-71. 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: 400-2. 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
Notes
*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.