Imatinib is currently the most popular targeted therapy for CML. The leukemia is associated with the abnormal fusion of BCR with a kinase gene, ABL, which results in a perpetually active kinase known as BCR-ABL. Imatinib, a tyrosine kinase inhibitor, slows down the spread of cancer by blocking BCR-ABL activity. But the drug doesn't work in everyone and patients often relapse, most likely because the drug only targets mature cells, leaving CML stem cells behind. Scientists have therefore been hunting for complementary therapies that act on pathways left undeterred by kinase inhibitors.
Mutated versions of the recently identified protein AHI-1, whose function is unknown, have been shown to be highly expressed in leukemic stem cells—the same cells that express BCR-ABL in patients with CML. Here, Zhou et al. show that expressing AHI-1 in stem cells turns the cells cancerous in vitro, and these cells caused lethal leukemia when transferred into mice. When expressed in BCR-ABL–positive cells, AH1-1 exacerbated the growth-promoting effects of the fusion protein.
AHI-1's growth-promoting activity was attributed to the ability of AHI-1 to bind to BCR-ABL, along with an activated version of the downstream signaling protein JAK2. Cells expressing this complex were resistant to the kinase-blocking action of imatinib. Indeed, blocking AHI-1 in cells from imatinib-resistant CML patients restored the cells' sensitivity to the drug.
With this finding, the race is on to find a drug to block AH1-1. As other studies have recently suggested, the cure for CML and other leukemias may not lie in a miracle drug, but rather in a carefully concocted cocktail of targeted therapies.