CaMKII γ, a critical regulator of CML stem/progenitor cells, is a target of the natural product berbamine

Bcr-Abl tyrosine kinase inhibitors (TKIs) have been a remarkable success for the treatment of Ph+ chronic myeloid leukemia (CML). However, a significant proportion of patients treated with TKIs develop resistance because of leukemia stem cells (LSCs) and T315I mutant Bcr-Abl. Here we describe the unknown activity of the natural product berbamine that efficiently eradicates LSCs and T315I mutant Bcr-Abl clones. Unexpectedly, we identify CaMKII gamma as a specific and critical target of berbamine for its antileukemia activity. Berbamine specifically binds to the ATP-binding pocket of CaMKII gamma, inhibits its phosphorylation and triggers apoptosis of leukemia cells. More importantly, CaMKII gamma is highly activated in LSCs but not in normal hematopoietic stem cells and coactivates LSC-related beta-catenin and Stat3 signaling networks. The identification of CaMKII gamma as a specific target of berbamine and as a critical molecular switch regulating multiple LSC-related signaling pathways can explain the unique antileukemia activity of berbamine. These findings also suggest that berbamine may be the first ATP-competitive inhibitor of CaMKII gamma, and potentially, can serve as a new type of molecular targeted agent through inhibition of the CaMKII gamma activity for treatment of leukemia. (Blood. 2012;120(24):4829-4839)