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CHRONIC MYELOPROLIFERATIVE NEOPLASMS

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

Leukemia volume 39, pages 876–887 (2025)Cite this article

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Abstract

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.

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Fig. 1: Socs2 is upregulated in HSCs from VF mice.
Fig. 2: Loss of Socs2 does not worsen the MPN disease course.
Fig. 3: Socs2 knockout increased pSTAT5 levels in mouse VF MPN cells.
Fig. 4: Socs2 knockout increased the proportion of MPN mice with pegIFNα -induced molecular response.
Fig. 5: Loss of Socs2 sensitized JAK2-V617F cells to pegIFNα-induced clonal depletion.
Fig. 6: VF;Socs2-/- HSC function from mice receiving pegIFNα was impaired.
Fig. 7: The SOCS2 inhibitor MN714 improves the efficacy of IFNα in reducing the output of CD34+ cells from PV patients in vitro.

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Acknowledgements

We thank the Flow Cytometry core facility of the Department of Biomedicine for help in cell sorting and flow cytometry analysis and the Genomics Facility of the University of Basel for the help with RNA preparation for single-cell and bulk RNAseq and members of the laboratory for helpful discussions and critical reading of our manuscript.

Funding

This work was supported by grants from the Swiss National Science Foundation (31003A_166613, 310030_185297/1, and 310030_185297/2), the Swiss Cancer Research foundation (KFS-3655-02-2015 and KFS-4462-02-2018), the Stiftung für Hämatologische Forschung, and the Cancer Prevention and Research Institute of Texas (CPRIT) RR240024 to RCS, and a grant from the Research Fund of the University of Basel for Junior Researchers to QK. Work in the A.C. Lab was supported by the Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under grant agreement no. 875510 (EUbOPEN project). The IMI2 Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program, European Federation of Pharmaceutical Industries and Associations (EFPIA) companies, and associated partners KTH, OICR, Diamond, and McGill.

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Authors and Affiliations

  1. Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel, Basel, Switzerland

    Marc Usart, Quentin Kimmerlin, Jan Stetka, Cédric Stoll, Shivam Rai, Tiago Almeida Fonseca, Riikka Karjalainen, Hui Hao-Shen & Radek C. Skoda

  2. Baylor College of Medicine, Dan L Duncan Comprehensive Cancer Center, Houston, TX, USA

    Marc Usart, Quentin Kimmerlin & Radek C. Skoda

  3. Department of Biomedicine, Bioinformatics, University of Basel and University Hospital Basel, Basel, Switzerland

    Julien Roux & Athimed El Taher

  4. Swiss Institute of Bioinformatics, Basel, Switzerland

    Julien Roux & Athimed El Taher

  5. Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee; 1 James Lindsay Place, Dundee, DD1 5JJ, UK

    Dylan Lynch, Nikolai Makukhin & Alessio Ciulli

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Contributions

MU designed and performed research, analyzed data and wrote the manuscript; QK, JS, CS, RK, SR, TAF and HHS performed research and analyzed data; JR and AET analyzed data, NM, DL and AC developed MN714 and analyzed data, and RCS designed research, analyzed data and wrote the manuscript.

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Correspondence to Radek C. Skoda.

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Competing interests

R.C.S. is a scientific advisor/SAB member and has equity in Ajax Therapeutics, he is a co-founder of MPNquest and he consulted for and/or received honoraria from Novartis, BMS/Celgene, AOP, GSK, Baxalta and Pfizer. M.U. is a co-founder of MPNquest. A.C. is a scientific founder and shareholder of Amphista Therapeutics, a company that is developing targeted protein degradation therapeutic platforms. The Ciulli laboratory receives or has received sponsored research support from Almirall, Amgen, Amphista Therapeutics, Boehringer Ingelheim, Eisai, Merck KaaG, Nurix Therapeutics, Ono Pharmaceutical and Tocris-Biotechne.

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Usart, M., Kimmerlin, Q., Stetka, J. et al. Loss of Socs2 improves molecular responses to IFNα in a mouse model of myeloproliferative neoplasms driven by JAK2-V617F. Leukemia 39, 876–887 (2025). https://doi.org/10.1038/s41375-025-02550-5

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