Gene:

ABL1

ABL proto-oncogene 1, non-receptor tyrosine kinase

The ABL1 gene is an important cancer PGx diagnostic pharmacogene as part of the BCR-ABL fusion protein (see drug label annotations for bosutinib, busulfan, dasatinib, homoharringtonine, imatinib, nilotinib, ponatinib).

The ABL1 proto-oncogene encodes a tyrosine kinase [Article:2676087]. In the 1980’s it was shown to be involved in the Philadelphia chromosome (Ph+), a translocation event that is characteristic of chronic myelocytic leukaemia, CML [Article:6960256]. The fusion of ABL1 and BCR results in an overactive tyrosine kinase [Article:2676087]. There is heterogeneity in the size of the BCR-ABL fusion proteins generated due to different breakpoints of the translocation. The breakpoints in the ABL gene on chromosome 9 occur usually at exon a2, the breakpoints in BCR on chromosome 22 are between exons e12–e16 (also known as b1–b5) [Article:25949834]. Some of the breakages too small to be seen by karyotype, ie classified as Ph-, but still harbor the BCR-ABL fusion protein [Article:25949834].

One of the first targeted anti-cancer therapies, imatinib, was developed by testing compounds that inhibited growth of BCR-ABL positive cell lines [Article:9345054]. Imatinib was approved in 2001 by the FDA for the treatment of CML 12941424. Imatinib binds to the ATP–binding site of the ABL kinase and stabilizes the protein in this inactive conformation [Article:15256671]. More than 100 different mutations in BCR-ABL have been reported that confer resistance to imatinib [Articles:25132497, 15256671]. The key residues in BCR-ABL are: M244, G250, Q252, Y253, E255, V299, F311, T315, F317, M351, F359, and H396 [Article:25132497]. Second generation ABL inhibitors such as desatinib were able to inhibit mutant ABL tyrosine kinases except for T315I [Article:15256671]. Ponatinib was recently approved to treat imatinib-resistant Ph+ leukemias including those with T315I [Article:25132497].