Mechanisms of imatinib-resistance in clinical patients and imatinib-resistant cell line showing over-expression of Lyn in chronic myelogenous leukemia (CML)

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(1) Analyses using clinical data and samples We analyzed total 142 CML patients in Hiroshima area Cytogenetic response was 94% of CCyR achievement at 60 months in fresh cases. Molecular responses were; 64% of MMR at 12 months, 90% of MMR, and 35% of CMR at 60 months in fresh cases. Administration dress in the first 6 months were analyzed. Patients receiving dose of less than 400mg/day revealed poorer response as compared to the patients who received more than 400mg/day. Patients receiving mom than 500mg/day showed better response in terms of achievement of 0 copy of BCR-ABL mRNA The decline of the BCR-ABL mRNA in the fast 3 months showed three-phase, which paralleled the BCR-ABL-FISH data Mutation of ABL gene was analyzed in total 42 patients, but mutation was absent Lyn mRNA was elevated in some of the CML patients during the course of imatinib treatment.(2) Analyses using cell lines: We established imatinib-sensitive (MYL) and resistant-(MYL-R) cell lines. ABL mutations were absent Imatinib stimulation caused phosphorylation of CrkL in the both, and caused apoptosis in MYL but not in MYL-R, suggesting that the mechanisms of resistance in MYL-R was imatinib-independent. Over-expressions of Lyn mRNA and protein were observed in MYL-R, but not in MYL Phosphorylations of JNK, ERK, STAT5, and Bim were observed MYL-R rather than MYL Both Src-family-kinase inhibitor and zoledronic acid suppressed the cell number in MYL-R Transfection of Lyn-siRNA in MYL-R demonstrated decrease of the cell number, decrease of the viable cells, increase of apoptotic cells, and partial recovery of imatinib-sensitivity-IFNα, zoledronic acid, PP2, CGP76030, FK228 showed synergistic effects with imatinib. Dasatinib also suppressed the phosphorylation of BCR-ABL in MYL-R cells. TKI-737 also suppressed the cell phosphorylation of MYL These results demonstrate that these new reagents have potential to overcome imatinib-resistance in CML.