Relation between resistance of Philadelphia-chromosome-positive acute lymphoblastic leukaemia to the tyrosine kinase inhibitor ST1571 and gene-expression profiles: a gene-expression study

Background The ABL tyrosine kinase inhibitor STI571 is a promising agent for treatment of advanced Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukaemia. However, resistance to this drug develops within a few months in most patients. We aimed to predict resistance to STI571. Methods Total RNA was extracted from 25 bone-marrow samples from 19 patients with Ph+ acute lymphoblastic leukaemia who were enrolled into a phase 11 study. 17 samples were obtained before STI571 treatment was started: ten from individuals who were classified as good responders to STI571 (sensitive), and seven from individuals who did not to respond to STI571 (primary resistance). Eight samples were obtained from patients during treatment with STI571. We analysed six matched samples, which were obtained before and during treatment with STI571. Oligonucleotide microarray analysis of samples was done with high-density microarrays. Findings We identified 95 genes whose expression could be used to predict sensitivity of leukaemic cells to STI571. On this basis, all the STI571-sensitive samples could clearly be distinguished from the resistant cases. 56 highly differentially expressed genes were identified in leukaemic cells that were secondarily resistant to STI571. Resistant leukaemic cells expressed high levels of Bruton's tyrosine kinase and two ATP synthetases (ATP5A1 and ATP5C1), and showed significantly reduced expression of the proapoptotic gene BAK1 and the cell-cycle control gene p15 INK4b, Interpretation We have shown the clinical relevance of gene expression data for the pretreatment assessment of acute lymphoblastic leukaemia. Our results have implications for future clinical studies of tyrosine kinase inhibitors.