Induction of apoptosis by directing oncogenic Bcr-Abl into the nucleus

// Zheng-Lan Huang 1,* , Miao Gao 1,* , Qian-Yin Li 1 , Kun Tao 1 , Qing Xiao 2 , Wei-Xi Cao 1 , and Wen-Li Feng 1 1 Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated by the Ministry of Education, Chongqing Medical University, Chongqing, People’s Republic of China. 2 Department of Hematology, The First Affiliated Hospital, Chongqing Medical University, Chongqing, People’s Republic of China. * These authors contributed equally to this work. Correspondence: Wen-Li Feng, email: // Keywords : chronic myeloid leukemia, Bcr-Abl, nuclear localization, rapalog, apoptosis Received : August 27, 2013 Accepted : October 7, 2013 Published : October 9, 2013 Abstract The chimeric Bcr-Abl oncoprotein, which causes chronic myeloid leukemia, mainly localizes in the cytoplasm, and loses its ability to transform cells after moving into the nucleus. Here we report a new strategy to convert Bcr-Abl to be an apoptotic inducer by altering its subcellular localization. We show that a rapalog nuclear transport system (RNTS) containing six nuclear localization signals directs Bcr-Abl into the nucleus and that nuclear entrapped Bcr-Abl induces apoptosis and inhibits proliferation of CML cells by activating p73 and shutting down cytoplasmic oncogenic signals mediated by Bcr-Abl. Coupling cytoplasmic depletion with nuclear entrapment of Bcr-Abl synergistically enhances the inhibitory effect of nuclear Bcr-Abl on its oncogenicity in mice. These results provide evidence that direction of cytoplasmic Bcr-Abl to the nucleus offers an alternative CML therapy.