Non drug targets were assigned an initial probability of 0. A diffusion process propagated those initial probabilities to the entire network integrating direct protein interactions of the drug targets and the global network topology. The diffusion was implemented as a modified random walk with restart. The initial probabilities were written as a vector x0 and the diffusion was computed by the iteration xi+1= Pxi+��x0, where P was a diffusion matrix derived from the PPI topology, �� was set to 0.3, and the iteration was run until convergence. The limit probability distribution, covering the whole PPI network, defined the treatment network model. This procedure has been shown to efficiently associate proteins to functionally related other proteins and it has the potential to capture synergistic effects arising from multiple targets of a single compound, which is a desirable characteristic for promiscuous small molecules such as the four kinase inhibitors considered here, Additional details, precise mathematical definitions, and proof of convergence are provided in Supplementary Methods. In this study we have addressed the question, which of the four second-generation TKI in clinial trials, nilotinib, dasatinib, bosutinib or bafetinib, has the most advantageous target profile in the context of Ph+ ALL. Ph+ ALL features a complex genetic background on top of the expression of the oncogenic tyrosine kinase BCR-ABL. This genetic complexity supposedly reduces the long-term effectiveness of BCR-ABL-directed therapy with imatinib. We therefore compared the four TKI in light of their impact on a Ph+ ALL PPI network, taking into account the additional gene copy number alterations that distinguish Ph+ ALL from CML rather than focussing on classical BCR-ABL signaling alone. We performed a network analysis based on a diffusion procedure. A similar approach has been employed recently to predict drug side effects with regard to heart arrhythmias. To this end, the authors were successful by focussing on the cognate drug targets. However, the well-documented pleiotropic nature of kinase inhibitors, which were the focus of interest here, made it necessary for our study to first determine the proteome-wide Ph+ ALL target profiles of each drug by chemical proteomics. Some of the KRX-0401 Akt inhibitor described genetic lesions in Ph+ ALL have been previously demonstrated to be also of functional relevance. For PF-04217903 c-Met inhibitor instance, IKAROS, encoded by IKZF1, has been shown to redirect BCR-ABL signaling from SFK activation to SLP65, which is downstream of the pre-B cell receptor tumor suppressor. In this way, loss of IKAROS promotes oncogenic signaling of BCR-ABL in part by phosphorylation and activation of the SRC family kinases LYN, HCK and FGR. These kinases have been previously demonstrated to be required for induction of Ph+ ALL while being dispensable for CML. In a similar way, BTK has been shown to be constitutively activated by BCR-ABL in Ph+ ALL cells thereby bypassing the pre-B cell receptor and providing a continuous survival signal.