https://orcid.org/0000-0002-0046-3254
Key points
TYK2 is essential for the amelioration of MPN features by IFN-α
The mechanism of IFN-α action is different between Jak2V617F HSCs and Jak2V617F progenitors
Abstract
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. Jak2V617F transgenic mice develop MPNs resembling human primary myelofibrosis, and ropeginterferon-α-2b ameliorated their features. However, these IFN-α effects were absent in Jak2V617F;Tyk2-/- mice. In mixed WT/Jak2V617F chimeric mice, IFN-α treatment induces Jak2V617F hematopoietic stem cells (HSCs) to enter the cell cycle and skew their differentiation into the megakaryocyte lineage, decreasing the number of Jak2V617F HSCs. The effects of IFN-α on Jak2V617F HSCs were not observed in mixed WT/Jak2V617F;Tyk2-/- mice, indicating that TYK2 is essential for the effects of IFN-α on both Jak2V617F progenitors and HSCs. The mechanism of IFN-α in Jak2V617F HSCs and progenitors differed: genes regulating the cell cycle were enriched in IFN-α-stimulated Jak2V617F HSCs, but not in Jak2V617F progenitors; genes regulating antiproliferation were enriched in IFN-α-stimulated Jak2V617F progenitors, but not in Jak2V617F 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 Jak2V617F cells were preserved in Jak2V617F;Stat1-/- mice, but to a moderate degree compared to Jak2V617F mice. Our study reveals essential roles of TYK2 for the preferential suppressive effect of IFN-α on Jak2V617F progenitors and HSCs.
Author notes
Data sharing statement:
Gene expression datasets obtained from mouse samples will be deposited at the DNA Data Bank of Japan. For data sharing requests, please contact Kazuya Shimoda (kshimoda@med.miyazaki-u.ac.jp).
