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<p>Therapy with pegylated interferon alpha (pegIFNα) can induce a deep molecular response in a subset of patients with myeloproliferative neoplasms (MPN). Here we investigated the role of <i>Socs2</i>, a negative regulator of cytokine signaling, in modulating the response to pegIFNα in a <i>JAK2</i>-V617F mouse model of MPN. Deleting <i>Socs2</i> in JAK2-V617F mice resulted in increased sensitivity to cytokines, without causing significant alterations in the MPN phenotype. When subjected to pegIFNα, the loss of <i>Socs2</i> enhanced the depletion of <i>JAK2</i>-mutant hematopoietic stem cells (HSCs), evidenced by reduced chimerism in peripheral blood and bone marrow compared to vehicle controls. Additionally, pegIFNα-treated <i>Socs2</i>-deficient <i>JAK2</i>-mutant HSCs exhibited functional impairments in secondary transplantations, reflecting long-term detrimental decline of their stemness. These findings demonstrate that loss of <i>Socs2</i> enhances the effectiveness of pegIFNα in depleting the <i>JAK2</i>-mutant HSC clone. In line with the genetic ablation of <i>Socs2</i>, the SOCS2 inhibitor MN714 combined with IFNα exhibited better efficacy than IFNα alone in reducing the output of CD34+ cells from PV patients in vitro. Targeting <i>SOCS2</i> could therefore improve therapeutic responsiveness in MPN patients receiving interferon therapy.</p>

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

  • 期刊论文

  • 发表日期：

    2025年3月11日

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  • Marc Usart,
  • Quentin Kimmerlin,
  • Jan Stetka,
  • Cédric Stoll,
  • Shivam Rai,
  • Tiago Almeida Fonseca,
  • Riikka Karjalainen,
  • Hui Hao-Shen,
  • Julien Roux,
  • Athimed El Taher,
  • Dylan Lynch,
  • Nikolai Makukhin,
  • Alessio Ciulli,
  • Radek C. Skoda

摘要

Therapy with pegylated interferon alpha (pegIFNα) 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 pegIFNα 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 pegIFNα, 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, pegIFNα-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 pegIFNα in depleting the JAK2-mutant HSC clone. In line with the genetic ablation of Socs2, the SOCS2 inhibitor MN714 combined with IFNα exhibited better efficacy than IFNα 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.