Difference between revisions of "BCR"

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==Synonyms==
 
==Synonyms==
  
BCR, RhoGEF and GTPase activating protein; Breakpoint Cluster Region; BCR1; ALL; CML; PHL; D22S11; D22S662
+
BCR, RhoGEF and GTPase activating protein; Breakpoint Cluster Region; BCR1; ALL; CML; PHL; D22S11; D22S662
  
 
==Genomic Location==
 
==Genomic Location==
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==Cancer Category/Type==
 
==Cancer Category/Type==
  
'''[http://www.ccga.io/index.php/Chronic_Myeloid_Leukemia_(CML)_with_t(9;22)(q34.1;q11.2);_BCR-ABL1 Chronic Myeloid  Leukemia]''' (also referred as (Chronic Myelogenous Leukemia)
+
'''[http://www.ccga.io/index.php/Chronic_Myeloid_Leukemia_(CML)_with_t(9;22)(q34.1;q11.2);_BCR-ABL1 Chronic Myeloid  Leukemia with BCR-ABL1]''' (also referred as Chronic Myelogenous Leukemia)
 +
 
 +
More than 90% of patients diagnosed with Chronic Myeloid Leukemia have 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 '''[http://www.omim.org/entry/613065 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].
  
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 '''[http://www.omim.org/entry/613065 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)
 
  
 
'''[http://www.ccga.io/index.php/Acute_lymphoblastic_leukaemia_(ALL) Acute Lymphoblastic Leukemia]'''
 
'''[http://www.ccga.io/index.php/Acute_lymphoblastic_leukaemia_(ALL) Acute Lymphoblastic Leukemia]'''
  
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 '''[http://www.omim.org/entry/613065 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).
+
Approximately 20% of patients (25 - 30% of adults and 2 - 10% of children) diagnosed with Acute Lymphoblastic Leukemia have 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 '''[http://www.omim.org/entry/613065 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==
+
'''[http://www.ccga.io/index.php/HAEM5:Mixed-phenotype_acute_leukaemia_with_BCR::ABL1_fusion Mixed Phenotype Acute Leukemia (MPAL) with BCR-ABL1]'''
  
The function of the normal BCR gene product is as a GTPase-activating protein for RAC1 and CDC42Promotes the exchange of RAC or CDC42-bound GDP by GTP, thereby activating them.  The protein has serine/threonine kinase activity.  (9)
+
BCR-ABL1 translocations (Ph+) are more prevalent in adult vs. pediatric patients diagnosed as Mixed Phenotype Acute Leukemia (MPAL) [16,17]The BCR-ABL1 translocations are considered to be prognostic of poorer outcomes in the context of patients diagnosed with Mixed Phenotype Acute Leukemia (MPAL) [16].  However, a number of individual studies indicate that Ph+ MPAL patients can be treated successfully with tyrosine kinase inhibitors (TKI) such as Imatinab and second generation TKIs [18,19].
  
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).
+
'''[http://www.ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_BCR::ABL1_fusion Acute Myeloid Leukemia with BCR-ABL1]'''
  
See the '''[http://www.ccga.io/index.php/BCR "ABL1 gene"]''' for additional details of the BCR-ABL1 gene fusion.
+
This rare entity, accounting for <1% of AML and <1% of BCR-ABL1 positive acute and chronic leukemias, typically occurs in adults.  AML with BCR-ABL1 is aggressive with poor response to traditional AML therapy or isolated tyrosine kinase (TK) therapy alone; TK therapy with subsequent allogeneic hematopoietic cell transplantation may improve survival [20].
  
==Common Alteration Types==
+
==Gene Overview==
  
By far the most common ABL1 alteration associated with cancer is the BCR-ABL1 fusion, 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.
+
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.
  
A number of other gene fusion partners have been identified with ABL1 and linked to other hematological cancers, but at a much smaller prevalence than BCR-ABL1.
+
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].
  
A small number of individual patients have been described with a BCR-JAK2 (Janus Kinase 2) fusion gene leading to Chronic myeloid leukemia (CML) and other hematological neoplasms, but this fusion gene appears to be rare (12, 13, 14).
+
See the '''[http://www.ccga.io/index.php/ABL "ABL1 gene"]''' for additional details of the BCR-ABL1 gene fusion.
  
BCR-FGFR1
+
==Common Alteration Types==
  
BCR-PDCFRA
+
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 '''[http://atlasgeneticsoncology.org/Anomalies/t0922p24q11ID1331.html] 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 '''[https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=BCR 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.
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
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! Copy Number Loss  !! Copy Number Gain  !!  LOH  !!  Loss-of-Function Mutation  !!  Gain-of-Function Mutation  !!  Translocation/Fusion  
 
! 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
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|   ||   ||   || || X || X
 
|}
 
|}
  
 
==Internal Pages==
 
==Internal Pages==
  
Put your text here
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'''[http://www.ccga.io/index.php/Chronic_Myeloid_Leukemia_(CML)_with_t(9;22)(q34.1;q11.2);_BCR-ABL1 Chronic Myeloid  Leukemia]'''
+
 
EXAMPLE [[Germline Cancer Predisposition Genes]]
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'''[http://www.ccga.io/index.php/Acute_lymphoblastic_leukaemia_(ALL) Acute Lymphoblastic Leukemia]'''
 +
 
 +
'''[http://www.ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_BCR::ABL1_fusion Acute Myeloid Leukemia (AML) with BCR-ABL1]'''
  
==External Links==
+
'''[http://www.ccga.io/index.php/HAEM5:Mixed-phenotype_acute_leukaemia_with_BCR::ABL1_fusion Mixed Phenotype Acute Leukemia (MPAL) with t(9;22)(q34.1;q11.2); BCR-ABL1]'''
  
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.
+
See the '''[http://www.ccga.io/index.php/ABL1 "ABL1 gene"]''' for additional details of the BCR-ABL1 gene fusion.
  
EXAMPLES
+
==External Links==
  
 
'''[http://atlasgeneticsoncology.org//Genes/BCRID55.html ''BCR'' by Atlas of Genetics and Cytogenetics in Oncology and Haematology]''' - detailed gene information
 
'''[http://atlasgeneticsoncology.org//Genes/BCRID55.html ''BCR'' by Atlas of Genetics and Cytogenetics in Oncology and Haematology]''' - detailed gene information
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'''[http://www.genecards.org/cgi-bin/carddisp.pl?gene=bcr ''BCR'' by GeneCards]''' - general gene information and summaries
 
'''[http://www.genecards.org/cgi-bin/carddisp.pl?gene=bcr ''BCR'' by GeneCards]''' - general gene information and summaries
 +
 +
'''[https://www.ncbi.nlm.nih.gov/gene/613 ''BCR'' by NCBI Gene]''' - general gene information and summaries
  
 
'''[http://omim.org/entry/151410 ''BCR'' by OMIM]''' - compendium of human genes and genetic phenotypes
 
'''[http://omim.org/entry/151410 ''BCR'' by OMIM]''' - compendium of human genes and genetic phenotypes
 +
 +
'''[https://databases.lovd.nl/shared/genes/BCR  ''BCR'' by LOVD(3)]''' - Leiden Open Variation Database
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 +
'''[http://www.unav.es/genetica/TICdb/results.php?hgnc=BCR ''BCR'' by TICdb]''' - database of Translocation breakpoints In Cancer
  
 
==References==
 
==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
+
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
+
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. 22:247-306PMID 15032571 DOI: 10.1146/annurev.immunol.22.012703.104753
+
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
+
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, 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
+
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, 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
+
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: 4392-9.  PMID 18628453 DOI: 10.1158/1078-0432.CCR-08-0117
+
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: 469-71.  PMID 19075254 DOI: 10.1200/JCO.2008.19.8853
+
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: 400-2. PMID 1903516 DOI: 10.1038/351400a0
+
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. 11:1553-1565PMID: 1705008
+
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
+
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.
 +
 
 +
16. Charles NJ and Boyer DF, (2017). Mixed-Phenotype Acute Leukemia: Diagnostic Criteria and Pitfalls. Arch Pathol Lab Med. 141:1462-1468. PMID 29072953. doi: 10.5858/arpa.2017-0218-RA.
 +
 
 +
17. Manola KN, (2013). Cytogenetic abnormalities in acute leukaemia of ambiguous lineage: an overview. Br J Haematol. 163:24-39. PMID 23888868. doi: 10.1111/bjh.12484.
 +
 
 +
18. Wolach O and Stone RM, (2014). How I treat mixed-phenotype acute leukemia. Blood 125:2477-2485. PMID 25605373. DOI: 10.1182/blood-2014-10-551465.
 +
 
 +
19. Kawajiri C, et al., (2014). Successful treatment of Philadelphia chromosome-positive mixed phenotype acute leukemia by appropriate alternation of second-generation tyrosine kinase inhibitors according to BCR-ABL1 mutation status. Blood 99:513-518. PMID 24532437. DOI: 10.1007/s12185-014-1531-0.
 +
 
 +
20. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p140.
  
 
== Notes ==
 
== Notes ==
 
<nowiki>*</nowiki>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.
 
<nowiki>*</nowiki>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.
 +
 +
[[Category:Cancer Genes B]]

Latest revision as of 13:50, 12 December 2023

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 with BCR-ABL1 (also referred as Chronic Myelogenous Leukemia)

More than 90% of patients diagnosed with Chronic Myeloid Leukemia have 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].


Acute Lymphoblastic Leukemia

Approximately 20% of patients (25 - 30% of adults and 2 - 10% of children) diagnosed with Acute Lymphoblastic Leukemia have 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].


Mixed Phenotype Acute Leukemia (MPAL) with BCR-ABL1

BCR-ABL1 translocations (Ph+) are more prevalent in adult vs. pediatric patients diagnosed as Mixed Phenotype Acute Leukemia (MPAL) [16,17]. The BCR-ABL1 translocations are considered to be prognostic of poorer outcomes in the context of patients diagnosed with Mixed Phenotype Acute Leukemia (MPAL) [16]. However, a number of individual studies indicate that Ph+ MPAL patients can be treated successfully with tyrosine kinase inhibitors (TKI) such as Imatinab and second generation TKIs [18,19].


Acute Myeloid Leukemia with BCR-ABL1

This rare entity, accounting for <1% of AML and <1% of BCR-ABL1 positive acute and chronic leukemias, typically occurs in adults. AML with BCR-ABL1 is aggressive with poor response to traditional AML therapy or isolated tyrosine kinase (TK) therapy alone; TK therapy with subsequent allogeneic hematopoietic cell transplantation may improve survival [20].

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

Chronic Myeloid Leukemia

Acute Lymphoblastic Leukemia

Acute Myeloid Leukemia (AML) with BCR-ABL1

Mixed Phenotype Acute Leukemia (MPAL) with t(9;22)(q34.1;q11.2); BCR-ABL1

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 NCBI Gene - general gene information and summaries

BCR by OMIM - compendium of human genes and genetic phenotypes

BCR by LOVD(3) - Leiden Open Variation Database

BCR by TICdb - database of Translocation breakpoints In Cancer

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.

16. Charles NJ and Boyer DF, (2017). Mixed-Phenotype Acute Leukemia: Diagnostic Criteria and Pitfalls. Arch Pathol Lab Med. 141:1462-1468. PMID 29072953. doi: 10.5858/arpa.2017-0218-RA.

17. Manola KN, (2013). Cytogenetic abnormalities in acute leukaemia of ambiguous lineage: an overview. Br J Haematol. 163:24-39. PMID 23888868. doi: 10.1111/bjh.12484.

18. Wolach O and Stone RM, (2014). How I treat mixed-phenotype acute leukemia. Blood 125:2477-2485. PMID 25605373. DOI: 10.1182/blood-2014-10-551465.

19. Kawajiri C, et al., (2014). Successful treatment of Philadelphia chromosome-positive mixed phenotype acute leukemia by appropriate alternation of second-generation tyrosine kinase inhibitors according to BCR-ABL1 mutation status. Blood 99:513-518. PMID 24532437. DOI: 10.1007/s12185-014-1531-0.

20. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. Revised 4th Edition. IARC Press: Lyon, France, p140.

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