Mutations were identified in 60 (60%) of these patients (all with imatinib-resistant CML-AP). Among the 60 patients with mutations, 26 unique imatinib-resistant mutations were identified, of which G250E was the most common (n = 9) (Table 5).

In our study, we investigated the activity of bosutinib, dasatinib, imatinib, and nilotinib against a panel of 18 mutated forms of BCR/ABL associated with imatinib resistance in CML and Ph+ acute lymphoblastic leukemia patients. The results are listed in Figure 1 (Table 1 lists all the actual values for the relative concentration that inhibits 50%).

When expressed in COS7 cells, the BCR/ABL construct with either E255K or T315I exhibited not only the resistance to imatinib but also the increase in activity to induce autophosphorylation...These results raise a possibility that the major imatinib resistance mutations E255K and T315I may confer the growth advantage on leukemic cells to expand in the absence of selective pressure from imatinib treatment.

Overall, these data indicate that the ENU-based assay faithfully reproduces the spectrum of mutations seen in patients with clinical resistance to imatinib mesylate...Spectrum and frequency of BCR-ABL kinase domain mutations recovered in the presence of imatinib mesylate, nilotinib, and dasatinib...Although both dasatinib and nilotinib are much more potent than imatinib mesylate and have activity against most kinase domain mutants, it is conceivable that their specific modes of binding to Abl may lead to new “vulnerable” sites that could confer drug resistance.