Background: The Jak2-V617F mutation is frequently found in MPN. The bone marrow micro-environment of MPN patients constitutes high levels of TNFα, IFNγ and IL-6. Since resistance to drug agents is of great clinical relevance, we teased the impact of the individual cytokines on drug efficacy. Methods: To predict the response to the JAK2 inhibitor class of agents, we (1) employed predictive simulation to model JAK2 bearing cell lines (2) identified novel synergistic combinations of Bcl-2 and JAK2 inhibitors against this JAK2 driven pathogenesis, (3) simulated the impact of TNFα and IFNγ on growth and proliferation and (4) validated the outcomes on Jak2 mutant cells. We used a previously characterized JAK2 small molecule inhibitor, G6, which exhibits significant efficacy in Jak2-V617F-mediated MPN and ABT737 was the selected Bcl-2 agent. The predictive simulation approach from Cellworks provides a representation of disease physiology incorporating signaling and metabolic networks with an integrated phenotype view. We modeled the JAK2-V617F expressing HEL and SET-2 cell lines along with G6 and ABT737. We then screened prospectively these agents, both individually and in combination, and with and without the microenvironment inflammatory cytokines. Results: The simulation identified a dose response based synergistic impact of the combination of G6 and ABT737 on cell proliferation and viability.TNFα increased the sensitivity of the single drug agents and their combinations. IFNγ sensitized the drug action further beyond a certain dose threshold. IL-6 did not show any impact on the cells due to lack of IL-6 signaling within these cells. Simulation studies though have predicted IL-6 induced resistance to these drug agents and possibly cancelling out the positive impact of TNFα and IFNγ clinically. Conclusions: Thus, this study validates the impact of the micro-environment on drug response and the use of simulation based technology to predict patient responses to drug agents. By accurately predicting responses of a patient’s cells to targeted agents a priori, the in silico simulation model provides an innovative approach to precision medicine for Jak2-mediated MPN.