TYK2 is essential for the therapeutic effect of IFN-α in Jak2V617F-induced murine myeloproliferative neoplasms

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• TYK2 is essential for the amelioration of MPN features by IFN-α • The mechanism of IFN-α action is different between Jak2 V617F HSCs and Jak2 V617F progenitors Interferon (IFN)-α exhibits antiviral and antiproliferative effects on normal and neoplastic cells. Intracellular signaling of IFN-α is mediated by tyrosine kinase-2 (TYK2) and janus kinase-1, followed by signal transducers and activators of transcription (STATs). TYK2 is redundant for the antiviral effect of IFN-α; however, the requirements for antiproliferative effects are unknown. We assessed the role of TYK2 in the effects of IFN-α in myeloproliferative neoplasm (MPN) model mice. Jak2 V617F transgenic mice develop MPNs resembling human primary myelofibrosis, and ropeginterferon-α-2b ameliorated their features. However, these IFN-α effects were absent in Jak2 V617F; Tyk2 -/- mice. In mixed WT/ Jak2 V617F chimeric mice, IFN-α treatment induces Jak2 V617F hematopoietic stem cells (HSCs) to enter the cell cycle and skew their differentiation into the megakaryocyte lineage, decreasing the number of Jak2 V617F HSCs. The effects of IFN-α on Jak2 V617F HSCs were not observed in mixed WT/ Jak2 V617F; Tyk2 -/- mice, indicating that TYK2 is essential for the effects of IFN-α on both Jak2 V617F progenitors and HSCs. The mechanism of IFN-α in Jak2 V617F HSCs and progenitors differed: genes regulating the cell cycle were enriched in IFN-α-stimulated Jak2 V617F HSCs, but not in Jak2 V617F progenitors; genes regulating antiproliferation were enriched in IFN-α-stimulated Jak2 V617F progenitors, but not in Jak2 V617F HSCs. The major IFN-α signaling molecule activated by JAKs is STAT1, which is essential for the antiviral effect. Most effects of IFN-α on Jak2 V617F cells were preserved in Jak2 V617F; Stat1 -/- mice, but to a moderate degree compared to Jak2 V617F mice. Our study reveals essential roles of TYK2 for the preferential suppressive effect of IFN-α on Jak2 V617F progenitors and HSCs.

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