The expected benefits from a new kind of drug presently in clinical trials for treatment of chronic myeloid leukemia (CML) is questioned in a study published online this week in Nature Chemical Biology. Formation of the BCR-ABL fusion oncoprotein is the defining molecular event in CML. Inhibition of the activity of this oncoprotein by targeted drugs, such as imatinib, has improved outcomes for patients with CML, but resistance to imatinib can ultimately become a problem. Another important event in CML is the activation of the gene regulatory factor STAT5. In normal and some malignant cell types, STAT5 is activated by the kinase JAK2. Because of this linkage, JAK2 inhibitors have been developed as drugs and are currently in clinical trials for CML. Giulio Superti-Furga, Veronika Sexl and colleagues show that the activity of some of these JAK2 inhibitors is independent of JAK2 expression and likely stems from the inhibition of BCR-ABL. This study suggests that in CML patients that have the BCR-ABL gene fusion, JAK2 may not be the best molecular target.
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