However, the in vivo efficacy of proteasome inhibitors on CML remains obscure, and whether proteasome inhibitors could exert synergistic/additive effects with IM needs more in-depth analysis. In this study, we investigated the combined effects of BOR/PSI with IM on CML in vivo and in vitro. Intriguingly, the results showed that the combinatory regimens yielded enhanced therapeutic efficacies in CML murine models, potentiated effects on CML cells, and triggered Palbociclib positive feedback signal networks involving BCR-ABL, b-catenin, protein phosphatase 2A, NFkB and Bruton’s tyrosine kinase, suggesting potential benefits of IM/BOR for CML patients. IM at low concentration attenuates heart and kidney damages in hypertensive rats, prevents the development of atherosclerotic lesions and diabetes-induced inflammatory cytokine overexpression in the aorta, and reverse experimental pulmonary AMN107 Src-bcr-Abl inhibitor hypertension in mice. However, at high dose IM causes severe congestive heart failure in mice and in a small portion of patients. Furthermore, dynamics of CML disease progression suggests that additional agents will be beneficial to eradicate CML leukemia stem cells. Since cells expressing BCR-ABL showed significantly higher proteasome levels than did BCR-ABL-negative cells and were more sensitive to induction of apoptosis by proteasome inhibitor, we test the combined effects of IM and proteasome inhibitors and report here that in vivo IM/BOR combination causes an intensified therapeutic efficacy without obvious toxicity, providing an alternative option for CML treatment. We show that IM in combination with proteasome inhibitor significantly prolongs life span of BALB/c mice bearing BCRABL/GFP-expressing murine hematopoietic cells, and suppresses tumor growth in nude mice harboring K562 cells. In vitro, IM/BOR and IM/PSI exhibit an enhanced inhibition of long-term colony forming activity and short-term cell growth of CD34+ cells from CML patients at CP or BC, cause potentiated proliferation inhibition in K562 and 32D cells expressing BCR-ABL, and exert significantly potentiated apoptotic effects on CML cells. Heaney et al recently demonstrated that proteasome may be a relevant target for quiescent CML stem cells following tyrosine kinase inhibitor therapy, while proteasome inhibitor are capable of inducing CML stem cell specific apoptosis. Compared to normal cells, cancer cells often bear higher Dym and evade mitochondrial apoptosis. Normally, in response to cellular stress, the cell’s mitochondria are triggered to release cyto C into the cytosol which then binds to Apaf-1 and initiates the formation of apoptosome, leading to the activation of casp-9 and subsequent casp-3. The release of cyto C is tightly regulated by pro- and anti-apoptotic members of Bcl-2 family. In CML, BCR-ABL upregulates Bcl-2 and Bcl-XL through activation of STAT5, and inhibits release of cytochrome C and prevents caspase activation even after cyto C release, hence confering resistance to apoptosis to CML cells. Interestingly, IM/BOR and IM/PSI cause collapse of Dym, downregulation of pBCL-2, increase of cytoplasmic cyto C and activation of casp-9, -8 and -3. It is well-known that IM acts as a specific inhibitor of BCR-ABL. BOR and PSI significantly enhance IM-triggered suppression of pBCR-ABL and inhibition of its tyrosine kinase activity in vitro and in vivo. In consistence with a previous report, we show that activation of caspases by IM/ BOR and IM/PSI leads to catabolism of BCR-ABL, where caspase inhibitor not only reduces apoptosis but also inhibits degradation of BCR-ABL. IM/BOR and IM/PSI also downregulate pSTAT5. These data suggest that the combinatory regimens on one hand target the mitochondria, downregulate Bcl-2 and activate caspases, on the other hand inhibit BCR-ABL/STAT5 which might in turn potentiate downregulation of Bcl-2 and activation of caspases. Furthermore, activated caspases can enhance BCR-ABL catabolism and inactivation. Therefore, IM/BOR and IM/PSI may trigger a positive feedback apoptotic signaling network.