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HGNC Approved Gene Symbol: ABL2
Cytogenetic location: 1q25.2 Genomic coordinates (GRCh38): 1:179,099,330-179,229,677 (from NCBI)
Kruh et al. (1986) identified a novel oncogene, which they designated ARG, related to ABL (189980) in DNA sequences from human plasma. The detection of a novel 12-kb transcript from this gene in human normal and tumor cells established it as a new member of the tyrosine kinase family that is closely related to but distinct from ABL. Kruh et al. (1990) assembled a full-length ARG cDNA by using the partial ARG sequence as probe to screen cDNA libraries prepared from K562, M426, and A172 cells and monocytes. The deduced 1,182-amino acid ARG protein shows high similarity to ABL in overall structural architecture as well as in the sequence of the tyrosine kinase domain and the SH2 and SH3 domains. ARG, like ABL, is expressed as 2 transcripts that result from alternative splicing and encode alternative protein forms that differ only in their N termini and one of which contains a myristoylation site.
In mouse muscle and cultured myotube cells, Finn et al. (2003) showed that Abl1 and Abl2 are concentrated at the postsynaptic neuromuscular junction and are mediators of postsynaptic acetylcholine receptor (AChR) clustering downstream of agrin (103320) and MuSK (601296) signaling. The authors suggested that the Abl kinases influence cytoskeletal regulatory molecules important for synapse assembly and remodeling.
Kruh et al. (1986) localized the ABL2 sequence to chromosome 1q24-q25 by in situ hybridization and somatic cell analysis. A constitutional fragile site is located at 1q24-q25. Seldin and Kruh (1989) mapped the mouse homolog (Abl2) to chromosome 1 by analysis of segregation with other distal chromosome 1 genetic polymorphisms in a panel of DNAs from interspecific backcross mice. This defined a region of distal mouse chromosome 1 showing homology of synteny with human chromosome 1q21-q32.
ABL2/ETV6 Fusion Gene
The ETV6/TEL gene (600618) is rearranged in most patients with 12p13 translocations fused to a number of different partners. Cazzaniga et al. (1999) described a case of acute myeloid leukemia M4 with eosinophilia carrying a t(1;12)(q25;p13) that involved the ETV6 gene at 12p13. They found that a novel transcript, created by fusion between the ETV6 and ABL2 genes, resulted in a chimeric protein consisting of the helix-loop-helix oligomerization domain of ETV6 and the SH2, SH3, and protein tyrosine kinase domains of ABL2. The reciprocal transcript ABL2-ETV6 was also detected in the patient's RNA by RT-PCR, although at a lower expression level. This was the first report of ABL2 involvement in a human malignancy. The patient studied by Cazzaniga et al. (1999) had, in addition to the translocation t(1;12), rearrangement of the CBFB (121360) and MYH11 (160745) genes produced by a pericentric inversion of chromosome 16, which is frequently found in acute myeloid leukemia M4 with eosinophilia.
Iijima et al. (2000) demonstrated that the ARG gene (ABL2) is a partner with the ETV6 gene in an acute myeloid leukemia (AML-M3) cell line with a t(1;12)(q25;p13) translocation. They pointed out that ARG is a tyrosine kinase (TK) similar to other tyrosine kinases that partner with ETV6 in leukemogenesis. The fusion transcripts consisted of exon 1 to 5 of ETV6 and the 3-prime portion of ARG starting from exon 1B or exon 2, resulting in an open reading frame for a fusion protein consisting of the entire 5-prime 'pointed' (PNT) oligomerization domain of ETV6 and all of the functional domains of ARG including the TK domain. This was the same protein structure as identified in other ETV6 TK fusion proteins. The reciprocal ARG/ETV6 transcript was not expressed, and the normal ETV6 allele was not deleted or rearranged. Although the ABL gene was known to be involved in various malignancies, notably chronic myeloid leukemia, ARG had not previously been implicated in malignancies despite its high homology to ABL. The ETV6/ARG protein may be involved in the unique differentiation capacity of the cell line studied; it had a remarkable feature to differentiate to mature eosinophils in culture with all-trans retinoic acid and cytokines.
Cazzaniga, G., Tosi, S., Aloisi, A., Giudici, G., Daniotti, M., Pioltelli, P., Kearney, L., Biondi, A. The tyrosine kinase Abl-related gene ARG is fused to ETV6 in an AML-M4Eo patient with a t(1;12)(q25;p13): molecular cloning of both reciprocal transcripts. Blood 94: 4370-4373, 1999. [PubMed: 10590083]
Finn, A. J., Feng, G., Pendergast, A. M. Postsynaptic requirement for Abl kinases in assembly of the neuromuscular junction. Nature Neurosci. 6: 717-723, 2003. [PubMed: 12796783] [Full Text: https://doi.org/10.1038/nn1071]
Iijima, Y., Ito, T., Oikawa, T., Eguchi, M., Eguchi-Ishimae, M., Kamada, N., Kishi, K., Asano, S., Sakaki, Y., Sato, Y. A new ETV6/TEL partner gene, ARG (ABL-related gene or ABL2), identified in an AML-M3 cell line with a t(1;12)(q25;p13) translocation. Blood 95: 2126-2131, 2000. [PubMed: 10706884]
Kruh, G. D., King, C. R., Kraus, M. H., Popescu, N. C., Amsbaugh, S. C., McBride, W. O., Aaronson, S. A. A novel human gene closely related to the abl proto-oncogene. Science 234: 1545-1548, 1986. [PubMed: 3787260] [Full Text: https://doi.org/10.1126/science.3787260]
Kruh, G. D., Perego, R., Miki, T., Aaronson, S. A. The complete coding sequence of ARG defines the Abelson subfamily of cytoplasmic tyrosine kinases. Proc. Nat. Acad. Sci. 87: 5802-5806, 1990. [PubMed: 2198571] [Full Text: https://doi.org/10.1073/pnas.87.15.5802]
Seldin, M. F., Kruh, G. D. Mapping of Abll within a conserved linkage group on distal mouse chromosome 1 syntenic with human chromosome 1 using an interspecific cross. Genomics 4: 221-223, 1989. [PubMed: 2567701] [Full Text: https://doi.org/10.1016/0888-7543(89)90305-4]