SOCS1 function in BCR-ABL mediated myeloproliferative disease is dependent on the cytokine environment.

SOCS1 function in BCR-ABL mediated myeloproliferative disease is dependent on the cytokine environment.

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Treatment with tyrosine kinase inhibitors is the standard of care for Philadelphia chromosome positive leukemias.However the Pickup-Fee 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 Shorts 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.