• What is BCR-ABL1?
  • BCR-ABL1 in Chronic Myeloid Leukemia
  • BCR-ABL1 c.764A>T (E255V)
  • Clinical Trials

BCR-ABL1

BCR-ABL1 is a fusion gene usually formed via a t(9;22) (q34;q11) translocation (Faderl et al. 1999). This translocation results in the Philadelphia chromosome. In rare cases lacking the traditional t(9;22) translocation, other translocations result in the creation of the BCR-ABL1 fusion gene. These sometimes involve multiple chromosomes.

 

BCR-ABL1 is present in all cases of chronic myeloid leukemia, but it is also involved in other cancers.  These include pediatric B-cell acute lymphoblastic leukemia (3-5%), adult B-cell acute lymphoblastic leukemia (25-30%), acute myeloid leukemia (rare), and T-cell acute lymphoblastic leukemia (rare; De Braekeleer et al. 2011).

ABL1 kinase inhibitors have been developed as targeted therapies against BCR-ABL1 positive malignancies.

Related Pathways

Contributors: Aaron Shaver, M.D., Ph.D., Madan Jagasia, M.B.B.S., M.S.

Suggested Citation: Shaver, A., M. Jagasia. 2015. BCR-ABL1. My Cancer Genome https://www.padiracinnovation.org/content/disease/chronic-myeloid-leukemia/bcr-abl1/?tab=0 (Updated December 7).

Last Updated: December 7, 2015

BCR-ABL1 in Chronic Myeloid Leukemia

Presence of a BCR-ABL1 fusion gene is necessary for the pathogenesis of CML. In up to 95% of cases, a t(9;22) (q34;q11) translocation results in the BCR-ABL1 fusion gene (Faderl et al. 1999). This translocation results in the Philadephia chromosome. In rare CML cases lacking the traditional t(9;22) translocation, other translocations result in the creation of the BCR-ABL1 fusion gene, which sometimes involve multiple chromosomes.

ABL1 is a tyrosine kinase, and, in normal cells, it plays a role in cellular differentiation and regulation of the cell cycle. The BCR-ABL1 fusion gene creates a constitutively active tyrosine kinase, which leads to uncontrolled proliferation.

Imatinib is the first-generation ABL tyrosine kinase inhibitor, and it was approved by the FDA in 2001; label indications for CML include use in newly diagnosed adult and pediatric patients and in patients after failure of interferon-alpha therapy. While treatment responses to imatinib are often dramatic and lasting, 30–40% of patients will eventually need further treatment (Santos et al. 2011). In many but not all cases, this is due to the acquisition of point mutations in the tyrosine kinase domain of the BCR-ABL1 fusion gene, which renders the protein insensitive to the inhibitory effect of imatinib. This type of disease progression led to the development of second-line TKIs: dasatinib, nilotinib, and bosutinib. Dasatinib and bosutinib have the additional advantage of being inhibitors of SRC.

The second-generation TKIs, dasatinib, nilotinib, and bosutinib, are more potent than imatinib, and they were developed to treat cases of CML resistant to imatinib. Dasatinib and nilotinib are approved for use in CML in newly diagnosed adults, while dasatinib, nilotinib, and bosutinib are approved for use in adults with resistance or intolerance to prior therapy that included imatinib (FDA 2012). Soverini et al. (2011) made mutation-specific treatment decision recommendations that were adopted by NCCN (2012​). Recommendations based on preclinical data are as follows: for T315I, HSCT or clinical trial; for V299L, T315A, and F317L/V/I/C, consider nilotinib rather than dasatinib; for Y253H, E255K/V, and F359V/C/I, consider dasatinib rather than nilotinib; and for all other mutations, consider high-dose imatinib, dasatinib, or nilotinib.

Ponatinib is a third-line TKI, developed specifically to address imatinib resistance due to the BCR-ABL1 T315I resistance mutation. Ponatinib is currently being investigated in phase III clinical trials.

Contributors: Aaron Shaver, M.D., Ph.D., Madan Jagasia, M.B.B.S., M.S.

Suggested Citation: Shaver, A., M. Jagasia. 2013. BCR-ABL1 in Chronic Myeloid Leukemia. My Cancer Genome https://www.padiracinnovation.org/content/disease/chronic-myeloid-leukemia/bcr-abl1/ (Updated July 18).

Last Updated: July 18, 2013

BCR-ABL1 c.764A>T (E255V) Mutation in Chronic Myeloid Leukemia

Properties
Location of mutation P-loop region of the kinase domain (Exon 4; Ensembl)
Frequency of ABL1 mutations in CML 31% (COSMIC)
Frequency of BCR-ABL1 E255V mutation in BCR-ABL1-mutated CML 2.9% (COSMIC​)
Implications for Targeted Therapeutics
Response to imatinib Confers reduced sensitivitya
Response to dasatinib Retains sensitivityb
Response to nilotinib Confers reduced sensitivityb
Response to bosutinib Unknown at this timeb
Response to ponatinib Unknown at this timec

The E255V mutation results in an amino acid substitution at position 255 in BCR-ABL1, from a glutamic acid (E) to a valine (V). Presence of point mutations in BCR-ABL1 has been implicated as a mechanism for development of imatinib resistance (reviewed in Soverini et al. 2011).

a Imatinib was approved by the FDA in 2001; label indications include use in newly diagnosed adult and pediatric patients with CML and in patients after failure of interferon-alpha therapy (FDA 2012). In preclinical studies, E255V-mutated cell lines demonstrated decreased sensitivity to imatinib compared with CML cell lines wild type for mutations (Soverini et al. 2011).

b Dasatinib and nilotinib are approved for use in CML in newly diagnosed adults, while dasatinib, nilotinib, and bosutinib are approved for use in adults with resistance or intolerance to prior therapy that included imatinib (FDA 2011, 2012). In preclinical studies, E255V-mutated cell lines demonstrated decreased sensitivity to nilotinib and bosutinib, but comparatively little reduced sensitivity to dasatinib, compared with CML cell lines wild type for mutations (Soverini et al. 2011). Soverini et al. (2011) made mutation-specific treatment decision recommendations that were adopted by NCCN (2012). For E255V, the recommendation was to “consider dasatinib rather than nilotinib” for patients with imatinib-resistant CML.

c Ponatinib is currently being investigated in phase III clinical trials. In preclinical studies, E255V-mutated cell lines demonstrated decreased sensitivity to ponatinib compared to CML cell lines wild type for mutations (Soverini et al. 2011).

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Contributors: Aaron Shaver, M.D., Ph.D., Madan Jagasia, M.B.B.S., M.S.

Suggested Citation: Shaver, A., M. Jagasia. 2014. BCR-ABL1 c.764A>T (E255V) Mutation in Chronic Myeloid Leukemia. My Cancer Genome https://www.padiracinnovation.org/content/disease/chronic-myeloid-leukemia/bcr-abl1/224/ (Updated August 7).

Last Updated: August 7, 2014

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