Autochecked users, Comment administrators, Editors, Interface administrators, Reviewers, Suppressors, Administrators, Widget editors
1,874
edits
Changes
no edit summary
Brian Davis, PhD
Brian Davis, PhD
etc.
__TOC__
__TOC__
'''[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))
'''[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 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 '''[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 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].
'''[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 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 '''[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].
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].
'''[http://www.ccga.io/index.php/Acute_Myeloid_Leukemia_(AML)_with_BCR-ABL1 Mixed Phenotype Acute Leukemia (MPAL) with BCR-ABL1]'''
'''[http://www.ccga.io/index.php/HAEM5:Mixed-phenotype_acute_leukaemia_with_BCR::ABL1_fusion 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) [12,13]. The BCR-ABL1 translocations are considered to be prognostic of poorer outcomes in the context of patients diagnosed with Mixed Phenotype Acute Leukemia (MPAL) [12]. However, a number of individual studies indicate that Ph+ MPAL patients can be treated successfully wiht tyrosine kinase inhibitors (TKI) such as Imatinab and second generation TKIs [14,15].
BCR-ABL1 translocations (Ph+) are more prevalent in adult vs. pediatric patients diagnosed as Mixed Phenotype Acute Leukemia (MPAL) [12,13]. The BCR-ABL1 translocations are considered to be prognostic of poorer outcomes in the context of patients diagnosed with Mixed Phenotype Acute Leukemia (MPAL) [12]. 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 [14,15].
'''[http://www.ccga.io/index.php/Acute_Myeloid_Leukemia_(AML)_with_BCR-ABL1 Acute Myeloid Leukemia with BCR-ABL1]'''
'''[http://www.ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_BCR::ABL1_fusion 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 [16].
==Gene Overview==
==Gene Overview==
The ''ABL1'' gene encodes a non-receptor tyrosine kinase that is ubiquitously expressed and involved in a large number of cellular processes (see '''[https://www.ncbi.nlm.nih.gov/gene/25#reference-sequences "NCBI Gene]'''). By far the most prevalent ''ABL1'' 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 ''ABL1'' gene encodes a non-receptor tyrosine kinase that is ubiquitously expressed and involved in a large number of cellular processes (see '''[https://www.ncbi.nlm.nih.gov/gene/25#reference-sequences "NCBI Gene]'''). By far the most prevalent ''ABL1'' 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]. The ''ABL1'' and ''ABL2'' genes encode tyrosine kinases which share overlapping physiological roles, and ''ABL2'' somatic or amplification mutations are more common than similar mutations in ''ABL1'' [6].
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].
The ''ABL1'' and ''ABL2'' genes encode tyrosine kinases which share overlapping physiological roles, and ''ABL2'' somatic or amplification mutations are more common than similar mutations in ''ABL1'' [6].
See the '''[http://www.ccga.io/index.php/BCR "BCR gene"]''' for additional details of the BCR-ABL1 gene fusion.
See the '''[http://www.ccga.io/index.php/BCR "BCR gene"]''' for additional details of the BCR-ABL1 gene fusion.
A number of other gene fusion partners have been identified with ''ABL1'' that are linked to hematological cancers, but at a much smaller prevalence than BCR-ABL1.
A number of other gene fusion partners have been identified with ''ABL1'' that are linked to hematological cancers, but at a much smaller prevalence than BCR-ABL1.
* NUP214-ABL1 (associated with T-cell Acute Lymphoblastic Leukemia).
*NUP214-ABL1 (associated with T-cell Acute Lymphoblastic Leukemia).
* ETV6-ABL1 (associated with Chronic Myeloid Leukemia, T-cell Acute Lymphoblastic Leukemia, B-cell Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia), and EML (associated with T-cell Acute Lymphoblastic Leukemia).
*ETV6-ABL1 (associated with Chronic Myeloid Leukemia, T-cell Acute Lymphoblastic Leukemia, B-cell Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia), and EML (associated with T-cell Acute Lymphoblastic Leukemia).
Somatic mutations for ''ABL1'' have been found in Lung Squamous Cell Carcinomas patients (2%), Uterine Corpus Endometrioid Carcinoma patients (3%) and in less than 1% of patients with Breast Invasive Carcinoma, Ovarian Serous Cystadenocarcinoma, and Lung Adenocarcinoma [6].
Somatic mutations for ''ABL1'' have been found in Lung Squamous Cell Carcinomas patients (2%), Uterine Corpus Endometrioid Carcinoma patients (3%) and in less than 1% of patients with Breast Invasive Carcinoma, Ovarian Serous Cystadenocarcinoma, and Lung Adenocarcinoma [6].
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
! 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
|-
|-
| || || || || X || X
| || || || ||X||X
|}
|}
'''[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]'''
'''[http://www.ccga.io/index.php/Acute_Myeloid_Leukemia_(AML)_with_BCR-ABL1 Acute Myeloid Leukemia (AML) with BCR-ABL1]'''
'''[http://www.ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia_with_BCR::ABL1_fusion Acute Myeloid Leukemia (AML) with BCR-ABL1]'''
'''[http://www.ccga.io/index.php/Mixed_Phenotype_Acute_Leukemia_(MPAL)_with_t(9;22)(q34.1;q11.2);_BCR-ABL1 Mixed Phenotype Acute Leukemia (MPAL) with t(9;22)(q34.1;q11.2); BCR-ABL1]'''
'''[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]'''
See the '''[http://www.ccga.io/index.php/BCR "BCR gene"]''' for additional details of the BCR-ABL1 gene fusion.
See the '''[http://www.ccga.io/index.php/BCR "BCR gene"]''' for additional details of the BCR-ABL1 gene fusion.
'''[http://www.genecards.org/cgi-bin/carddisp.pl?gene=abl1 ''ABL1'' by GeneCards]''' - general gene information and summaries
'''[http://www.genecards.org/cgi-bin/carddisp.pl?gene=abl1 ''ABL1'' by GeneCards]''' - general gene information and summaries
'''[https://www.ncbi.nlm.nih.gov/gene/25#reference-sequences "ABL1" by NCBI Gene]''' - general gene information
'''[https://www.ncbi.nlm.nih.gov/gene/25#reference-sequences ''ABL1'' by NCBI Gene]''' - general gene information
'''[http://www.omim.org/entry/189980 ''ABL1'' by OMIM]''' - compendium of human genes and genetic phenotypes
'''[https://databases.lovd.nl/shared/genes/ABL1 ''ABL1'' by LOVD(3)]''' - Leiden Open Variation Database
'''[http://www.unav.es/genetica/TICdb/results.php?hgnc=ABL1 ''ABL1'' by TICdb]''' - database of Translocation breakpoints In Cancer
==References==
==References==
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. 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.
12. 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.
13. 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
13. 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.
14. 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
14. 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.
15. 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 99:513-8. PMID 24532437 DOI: 10.1007/s12185-014-1531-0
15. 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.
== Notes ==
16. 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==
<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 A]]