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Imatinib spells BAD news for Bcr/abl-positive leukemias

One of the medical success stories of the past decade has been the development of new agents to treat chronic myelogenous leukemia (CML). Building on earlier studies that identified the t(9;22) chromosomal translocation in CML, cloned the BCR/ABL fusion gene, and demonstrated the ability of the resulting kinase to transform cells, investigators identified imatinib mesylate as an inhibitor of that kinase, demonstrated that imatinib inhibits proliferation and survival of Bcr/abl-transformed hematopoietic cells in vitro and in vivo, and performed clinical trials showing unprecedented activity in chronic-phase CML (1). When the earliest trials of imatinib in aggressive-phase CML and Bcr/abl-driven acute lymphocytic leukemia revealed emergence of resistance as a problem, the contribution of point mutations in the BCR/ABL gene was demonstrated (2), and kinase inhibitors that are unaffected by some of these mutations, including the recently approved dasatinib and nilotinib, entered clinical testing (3). It is important to emphasize, however, that BCR/ABL mutations are found in only a subset of imatinib-resistant Bcr/abl-driven leukemias (4). In this issue of PNAS, a report by Kuroda et al. (5) not only provides new insight into the cytotoxic action of imatinib but also potentially identifies another mechanism of resistance and a means for overcoming it.