ABL1
Primary Author(s)*
Brian Davis, PhD
Synonyms
ABL proto-oncogene 1, non-receptor tyrosine kinase; Abelson tyrosine-protein kinase 1; ABL; JTK7; p150; c-ABL; v-abl; CHDSKM; c-ABL1; bcr/abl
Genomic Location
Cytoband: 9q34.12
Genomic Coordinates:
chr9:130,713,881-130,887,675(GRCh38/hg38)
chr9:133,589,268-133,763,062(GRCh37/hg19)
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 ABL1 gene encodes a non-receptor tyrosine kinase that is ubiquitously expressed and involved in a large number of cellular processes (see "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 "BCR gene" for additional details of the BCR-ABL1 gene fusion.
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.
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).
- 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].
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].
| Copy Number Loss | Copy Number Gain | LOH | Loss-of-Function Mutation | Gain-of-Function Mutation | Translocation/Fusion |
|---|---|---|---|---|---|
| X | X |
Internal Pages
See the "BCR gene" for additional details of the BCR-ABL1 gene fusion.
External Links
ABL1 by Atlas of Genetics and Cytogenetics in Oncology and Haematology - detailed gene information
ABL1 by COSMIC - sequence information, expression, catalogue of mutations
ABL1 by CIViC - general knowledge and evidence-based variant specific information
ABL1 by St. Jude ProteinPaint mutational landscape and matched expression data.
ABL1 by Precision Medicine Knowledgebase (Weill Cornell) - manually vetted interpretations of variants and CNVs
ABL1 by Cancer Index - gene, pathway, publication information matched to cancer type
ABL1 by OncoKB - mutational landscape, mutation effect, variant classification
ABL1 by My Cancer Genome - brief gene overview
ABL1 by UniProt - protein and molecular structure and function
ABL1 by Pfam - gene and protein structure and function information
ABL1 by GeneCards - general gene information and summaries
"ABL1" by NCBI Gene - general gene information
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.
Notes
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