XPO1 is a new target of homoharringtonine (HHT): Making NPMc plus AML cells much more sensitive to HHT treatment

Acute myeloid leukemia (AML) is a heterogeneous disease and about one third of AML patients carry nucleo-phosmin (NPM1) mutation. Because 95% mutations give NPM1 an additional nuclear export signaling (NES) and dislocate NPM1 in cytoplasm (NPMc+), relocating NPM1 in nucleus provide an innovative strategy for treating this type of AML. The nuclear export of NPM1 depends on the nuclear protein export receptor XPO1, which recognizes the NES sequence on NPM1. Homoharringtonine (HHT) is a first-line chemotherapy drug of AML, yet the exact mechanism of its anti-AML activity is elusive. In this study, we found that HHT can directly target XPO1 to its NES-binding cleft, bind to Cys528 of XPO1, and inhibits its nuclear transport function. In addition, HHT can block NPMc+ proteins nuclear export and thus make NPMc+ AML cells much more sensitive to HHT treatment. Furthermore, the sensitivity of NPMc+ AML cells to HHT is a universal phenomenon irrespective of the different genetic lesions of AML. Taken together, our findings suggest that XPO1 is a new target of HHT and provide a novel strategy for NPMc+ AML treatment.