Imatinib-resistant chronic myeloid leukemia (CML): Current concepts on pathogenesis and new emerging pharmacologic approaches

Chronic myeloid leukemia (CML) is a stem cell disease, in which the BCR/ABL oncoprotein is considered essential for abnormal growth and accumulation of neoplastic cells. During the past 10 years, the BCR/ABL tyrosine kinase inhibitor imatinib (STI571) has successfully been introduced in the treatment of the disease. However, intrinsic as well as acquired resistance against the drug have been described and have been recognized as an emerging problem and challenge in clinical practice, and a key issue in CML research. Most of the respective concepts focus on imatinib-resistant mutants of BCR/ABL that are detectable in a high proportion of cases. However, other factors also contribute to resistance against imatinib, including the genetic background, the biologic features of CML stem cells, gene amplifications, silencing of tumor suppressor genes, and various pharmacologic aspects. In this article, the mechanisms of resistance against imatinib and other BCR/ABL tyrosine kinase inhibitors in CML are discussed together with strategies to overcome and to prevent resistance with available drugs or with novel antileukemic approaches.