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 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)

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 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 ABL1 gene encodes for 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 parters, but especially with the BCR 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. 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. They include NUP214 (associated with T-cell Acute Lymphoblastic Leukemia), ETV6 (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). (6)

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. 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).

Common Alteration Types

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. 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. They include NUP214 (associated with T-cell Acute Lymphoblastic Leukemia), ETV6 (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).

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. 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)

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

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EXAMPLE Germline Cancer Predisposition Genes

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

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 120:1002-9, 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

Notes

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