Abstract

Case study of primary imatinib resistance and correlation of BCR-ABL multiple mutations in chronic myeloid leukemia

Author(s): Zafar Iqbal, Rubina T. Siddiqui, Javed A. Qureshi and Ahmad M. Khalid

Background: The kinase inhibitor, imatinib (Gleevec^™, Novartis) has proven to be an effective treatment for chronic myeloid leukemia, providing proof-of-principle for a molecularly targeted approach in oncology. Despite its success in BCR-ABL-positive chronic myeloid leukemia patients, primary imatinib resistance has emerged, resulting in disease relapse. Little is known about the underlying genetic causes of resistance, however, with emerging pharmacogenomic approaches, a more comprehensive picture is developing. In imatinib-resistant patients, point mutations have been detected in an ATP-binding domain of the ABL gene, which disturbs the binding of imatinib to this target leading to resistance. However, it remains to be determined whether these mutations confer primary imatinib resistance. Methods: Primary imatinib resistance was observed in a chronic myeloid leukemia patient with no hematological, cytogenetic and molecular response to 9 months treatment with 400 mg imatinib/day. A highly sensitive allele-specific oligonucleotide polymerase chain reaction was established to detect point mutations in BCR-ABL adenosine triphosphate-binding domain. Results: C944T and T1052C mutations were detected which cause complete and partial imatinib resistance, respectively. Conclusions: This is a case study of multiple point mutations conferring primary imatinib resistance in one patient at the same time. Elucidating the biological mechanisms of primary imatinib resistance will improve the ability to predict patient responsiveness and provide effective clinical management. Furthermore, the allele-specific oligonucleotide-polymerase chain reaction assay is very effective in detecting mutations related to imatinib resistance.