STI-571, a new Abl tyrosine kinase inhibitor recently approved by the Food and Drug Administration, is highly effective in treating the early stages of chronic myeloid leukemia (CML), but remissions induced in advanced phases tend to be relatively short-lived, an observation that suggests the development of de novo resistance to the drug (1, 2). Gorre et al.(3) showed that “acquired” resistance to STI-571 is usually associated with reactivation of the tyrosine kinase activity of the BCR-ABL oncoprotein; this was due to amplification of the gene in three patients and to a point mutation in the kinase domain of BCR-ABL in six cases. Although the former mechanism had been previously identified in CML cell lines (4–6), Abl mutations affecting the binding of STI-571 are novel. It is plausible that specific amino acid substitutions should lead to drug resistance, because crystallographic studies have shown that some amino acid residues within the ATP pocket of the kinase domain are essential for STI-571 binding. We find it surprising, however, that the same nucleotide change (ACT 3 ATT) was found in six of nine patients who developed STI-571 resistance. Like Gorre et al., we have been investigating the mechanisms of acquired resistance in clinical material from CML patients and acute leukemia patients positive for the Philadelphia (Ph) chromosome translocation who are receiving treatment with STI-571. We sequenced the BCR-ABL kinase domain from cells obtained from 12 patients who relapsed while receiving STI-571 and identified a functional point mutation in the kinase domain in only one case. This was a G 3 A change that results in a Glu 3 Lys substitution at position 255 of Abl. In none of the 12 cases did we find the Thr315Ile mutation identified by Gorre et al. Hochhaus et al. report similar findings in an accompanying comment, below; their study identified a different point mutation in the ATP binding site of BCR-ABL tyrosine kinase in one out of 32 patients studied, and none of their cases had the Thr315Ile substitution. The big difference in frequency of the Thr315Ile mutation between the North American study, which found the mutation in six of nine patients, and the two European studies, which found it in none of the 44 patients examined, is intriguing. Could it be due to differing ethnic or genetic backgrounds in the patient populations? Or were the individuals studied by Gorre et al.(3) heavily pretreated with high-dose radiotherapy or chemotherapy that increased the incidence of specific mutations? In either case, it would still be difficult to explain the finding of one unique nucleotide change in all the mutated cases without coexistence of at least some other mutations. The apparent “cluster of identical mutations” could be an artifact due to PCR contamination, but this is unlikely, because the sequence was confirmed in genomic DNA in some cases. Alternatively, one could argue that the negative results in the two European studies were due to low sensitivity of detection—also unlikely, because other, less frequent point mutations were readily identified in both patient cohorts. Thus, we believe that it is probably premature to assume that the main cause of resistance to STI-571 in CML patients is one specific mutation in the BCR-ABL kinase domain.