Development of an effective therapy for chronic myelogenous leukemia

Abstract

Targeted small-molecule drugs have revolutionized treatment of chronic myeloid leukemia (CML) during the last decade. These agents interrupt a constitutively active BCR-ABL, the causative agent for CML, by interfering with adenosine 5' triphosphate-dependent ABL tyrosine kinase. Although the efficacy of tyrosine kinase inhibitors (TKIs) has resulted in overall survival of greater than 90%, TKIs are not curative. Moreover, no currently approved TKIs are effective against the T315I BCR-ABL variant. However, a new generation of TKIs with activity against T315I is on the horizon. We will highlight the clinical utility of historical CML therapeutics, those used today (first- and second-generation TKIs), and discuss treatment modalities that are under development. Recent advances have illuminated the complexity of CML, especially within the marrow microenvironment. We contend that the key to curing CML will involve strategies beyond targeting BCR-ABL because primitive human CML stem cells are not dependent on BCR-ABL. Ultimately, drug combinations or exploiting synthetic lethality may transform responses into definitive cures for CML.

Figure 1. p210 BCR-ABL functional domains and effects of downstream signaling

BCR-ABL signaling leads to enhanced proliferation, reduced apoptotic potential, and altered cell adhesion. Contributions from both BCR and ABL domains on downstream signaling are illustrated. Dashed lines indicate additional intermediate signaling steps not detailed in this figure. CC, coiled-coil; S/T kinase, serine/theronine kinase; DH, Dbl homology; PH, Pleckstrin homology; SH2 or SH3, Src homology 2/3; Y kinase, tyrosine kinase; DBD, DNA binding domain; ABD, actin binding domain. (Figure courtesy of Andrew Dixon).