Demirel, ÖzlemBalló, OlivierReddy, Pavankumar N. G.Vakhrusheva, OlesyaZhang, JingEichler, AstridFernandes, RamonaBadura, SusanneServe, HubertBrandts, Christian2017-11-212017Demirel, Özlem, Olivier Balló, Pavankumar N. G. Reddy, Olesya Vakhrusheva, Jing Zhang, Astrid Eichler, Ramona Fernandes, Susanne Badura, Hubert Serve, and Christian Brandts. 2017. “SOCS1 function in BCR-ABL mediated myeloproliferative disease is dependent on the cytokine environment.” PLoS ONE 12 (7): e0180401. doi:10.1371/journal.pone.0180401. http://dx.doi.org/10.1371/journal.pone.0180401.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34375031Treatment with tyrosine kinase inhibitors is the standard of care for Philadelphia chromosome positive leukemias. However the eradication of leukemia initiating cells remains a challenge. Circumstantial evidence suggests that the cytokine microenvironment may play a role in BCR-ABL mediated leukemogenesis and in imatinib resistance. Gene expression analyses of BCR-ABL positive ALL long-term cultured cells revealed strong reduction of SOCS mRNA expression after imatinib treatment, thereby demonstrating a strong inhibition of cytokine signaling. In this study we employed SOCS1—a strong inhibitor of cytokine signaling—as a tool to terminate external cytokine signals in BCR-ABL transformed cells in vitro and in vivo. In colony formation assays with primary bone marrow cells, expression of SOCS1 decreased colony numbers under pro-proliferative cytokines, while it conferred growth resistance to anti-proliferative cytokines. Importantly, co-expression of SOCS1 with BCR-ABL led to the development of a MPD phenotype with a prolonged disease latency compared to BCR-ABL alone in a murine bone marrow transplantation model. Interestingly, SOCS1 co-expression protected 20% of mice from MPD development. In summary, we conclude that under pro-proliferative cytokine stimulation at the onset of myeloproliferative diseases SOCS1 acts as a tumor suppressor, while under anti-proliferative conditions it exerts oncogenic function. Therefore SOCS1 can promote opposing functions depending on the cytokine environment.en-USBiology and Life SciencesPhysiologyImmune PhysiologyCytokinesMedicine and Health SciencesImmunologyImmune SystemInnate Immune SystemDevelopmental BiologyMolecular DevelopmentGeneticsGene ExpressionOncologyCancers and NeoplasmsHematologic Cancers and Related DisordersLeukemiasHematologyCell BiologySignal TransductionCell SignalingSignal InhibitionExperimental Organism SystemsModel OrganismsMouse ModelsAnimal ModelsBiochemistryProteinsPost-Translational ModificationPhosphorylationSpleenBiology and life sciencesCell biologySignal transductionCell signalingSTAT signalingJournal Article2017-11-2110.1371/journal.pone.0180401