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Brian Davis, PhD

Brian Davis, PhD

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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))

 

'''[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].

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.

'''[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 with tyrosine kinase inhibitors (TKI) such as Imatinab and second generation TKIs [14,15].

 

 

'''[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].

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 ''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].

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.

==Common Alteration Types==

==Common Alteration Types==

By far the most common ABL1 alteration associated with cancer is the BCR-ABL1 fusion as described above in CML and ALL.  

By far the most common ''ABL1'' alteration associated with cancer is the BCR-ABL1 fusion as described above in CML and ALL.  

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].

Resistance to tyrosine kinase inhibitors (eg, Gleevec) are attributed to secondary mutations within the tyrosine kinase domain of ''ABL1'', especially the "gatekeeper" T315I residue mutation [7,8].

Resistance to tyrosine kinase inhibitors (e.g., Gleevec) are attributed to secondary mutations within the tyrosine kinase domain of ''ABL1'', especially the "gatekeeper" T315I residue mutation [7,8].

{| 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]'''

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

 

 

 

==References==

==References==

9. Diekmann D, et al., (1991). Bcr encodes a GTPase-activating protein for p21rac. Nature 35:400-402, 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 11:1553-1565, PMID: 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.

== 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.