Loss of Socs2 improves molecular responses to IFNa in a mouse model of myeloproliferative neoplasms driven by JAK2-V617F

Therapy with pegylated interferon alpha (pegIFNa) can induce a deep molecular response in a subset of patients with myeloproliferative neoplasms (MPN). Here we investigated the role of Socs2, a negative regulator of cytokine signaling, in modulating the response to pegIFNa in a JAK2-V617F mouse model of MPN. Deleting Socs2 in JAK2-V617F mice resulted in increased sensitivity to cytokines, without causing significant alterations in the MPN phenotype. When subjected to pegIFNa, the loss of Socs2 enhanced the depletion of JAK2-mutant hematopoietic stem cells (HSCs), evidenced by reduced chimerism in peripheral blood and bone marrow compared to vehicle controls. Additionally, pegIFNa-treated Socs2-deficient JAK2-mutant HSCs exhibited functional impairments in secondary transplantations, reflecting long-term detrimental decline of their stemness. These findings demonstrate that loss of Socs2 enhances the effectiveness of pegIFNa in depleting the JAK2-mutant HSC clone. In line with the genetic ablation of Socs2, the SOCS2 inhibitor MN714 combined with IFNa exhibited better efficacy than IFNa alone in reducing the output of CD34+ cells from PV patients in vitro. Targeting SOCS2 could therefore improve therapeutic responsiveness in MPN patients receiving interferon therapy. Overall design: We analyzed bone marrow c-kit+ cells from tamoxifen-inducible conditional JAK2-V617F transgenic mice (Scl;VF) and wild-type mice (WT). Individual mice were multiplexed using a hashtag oligonucleotide labeling strategy (TotalSeq-B). Sample demultiplexing can be performed using the information provided in the processed data file HTO_full_info.txt.