Genomic analysis identifies an incipient signature to forecast imatinib resistance before start of treatment in patients with chronic myeloid leukemia

Abstract

The unprecedented success of tyrosine kinase inhibitor (TKI), imatinib, to induce remission in 86 % of chronic phase (CP) patients of chronic myeloid leukemia (CML) is undermined by drug resistance. Few patients have primary resistance and do not respond to imatinib, while majority of them who respond must continue treatment to sustain the remission. This continued treatment increases the possibility of developing secondary resistance and these resistant patients progress to the acute phase of blast crisis (BC) wherein the survival is 7–11 months. However, if the patients who are at risk of developing resistance, can be identified before start of treatment with imatinib, they can be assisted with better treatment strategies. To identify markers to forecast imatinib resistance we chose to study chromosomal aberrations (CAs), as they are associated with causation, progression as well as drug resistance in CML. In this study, genomic DNA from CD34⁺ cells, isolated from healthy controls and CML patients in CP and BC before start of treatment, were subjected to array comparative genomic hybridization (aCGH). The number of CAs on distinct chromosomes identified by genomic analysis in CML-CP and -BC patients, were able to segregate the patients as imatinib-sensitive and -resistant in cluster analysis. The CP patients who misclassified into predominantly imatinib-resistant BC cluster were found to develop resistance during treatment. We thus report an incipient genomic signature which can forecast development of secondary resistance and upon validation in large cohort of patients has the potential for clinical application.