What Is the Basis for Resistance in the Current Era?
Persistence or re-emergence of Ph+ hematopoiesis continues to firmly define clinical resistance; when it occurs despite imatinib, or moreover ABL kinase inhibitors as a class, a large proportion of cases (generally in the rage of ~50%) have a consistent feature observed: acquisition of a point mutation in the Abl kinase domain. Other mechanisms are suspected in patients with wild-type ABL or those with Abl mutations predicted to respond to alternate kinase inhibitors who fail to respond. BCR-ABL amplification at the genomic or transcript level7,8 has been implicated in imatinib failure, overexpression of other tyrosine kinases such as the Scr-related LYN kinase has been observed in the case of BCR-ABL independent resistance,9 and variability in the amount and function of the drug influx protein OCT-1 has been linked to relative insensitivity to kinase inhibition by imatinib.10 It is certainly worthwhile to add to this list the notion of CML “stem cell resistance,” based in the ability
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