ABL1
In databases:
● Ensembl (http://www.ensembl.org/index.html): ENSG00000097007
● UniProt (http://www.uniprot.org/): P00519
● OMIM (http://www.ncbi.nlm.nih.gov/omim): 189980
● GeneCards (http://www.genecards.org/): ABL1
● HGNC (http://www.genenames.org/): 76 or ABL1
● Enzyme Number (IUBMB): EC 2.7.10.2
Gene locus:
9q34.1
Protein name:
v-abl Abelson murine leukemia viral oncogene homolog 1
Protein Size:
1130-1143 amino acids (from alternative splicing); about 145 kDa
Function:
The proto-oncogene ABL1 encodes a protein tyrosine kinase involved in cell differentiation, cell division, cell adhesion, and stress response. It interacts with a large variety of cellular proteins including signalling adaptors, kinases, phosphatases, cell cycle regulators, transcription factors and cytoskeletal proteins. Activity of ABL1 protein is negatively regulated by its SH3 domain, and deletion of the SH3 domain turns ABL1 into an oncogene.
Cancer-related gene alterations:
A t(9;22)(q34;q11) (translocation) involving ABL1 and BCR is a cause of chronic myeloid leukemia (CML). In fact, all CML patients have a t(9;22), at least at the molecular level. A similar translocation is found also in acute myeloid leukemia (AML) and in acute lymphoblastic leukemia (ALL).
In ALL, another translocation, t(9;12)(q34;p12) (ETV6-ABL1), may occasionally be observed. It fuses ETV6 N-terminus to the tyrosine kinase domain from ABL1 C-terminus.
In T-ALL, t(9;9)(q34;q34) (NUP214-ABL1) and t(9;14)(q34;q32) (EML1-ABL1) are also observed. The NUP214-ABL1 gene is the second most prevalent fusion gene involving ABL1 in malignant hemopathies.
In B-ALL t(1;9)(q24;q34) (RCSD1-ABL1), t(1;9)(p34;q34) (SFPQ-ABL1) and t(9;10)(q34;q22.3) (ZMIZ1-ABL1) are also observed.
Somatic ABL1 mutations have been observed mainly in haematopoietic and lymphoid tissue cancers (up to 30% of cases). They are substitutions, exclusively, and most of them are found in a region (amino acids 232-499) corresponding to protein kinase activity.
Specific therapies:
Due to the development of novel drugs able to target the enhanced tyrosine kinase activity of BCR-ABL, treatments have changed radically over the last 10 years. The first of these drug is imatinib mesylate which has become the first line therapy for all patients with CML
Recent data suggest that pharmacological inhibition of endogenous ABL could lead to a genetic instability, potentially by inhibition of mismatch repair mechanisms. Long-term inhibition of ABL by tyrosine kinase inhibitor therapies could therefore be responsible of the occurrence of a mutator phenotypes.
References (free access):
ABL1 fusion genes in hematological malignancies: a review. De Braekeleer E, Douet-Guilbert N, Rowe D, Bown N, Morel F, Berthou C, Férec C, De Braekeleer M. Eur J Haematol. 2011 May;86(5):361-71.
Genomic amplification of BCR/ABL1 and a region downstream of ABL1 in chronic myeloid leukaemia: a FISH mapping study of CML patients and cell lines. Virgili A, Nacheva EP. Mol Cytogenet. 2010 Sep 1;3:15.
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