TYK2 Is Essential for IFNα-Induced Resolution of MPN Features in a Murine Jak2V617F PMF Model

• Published in: Blood 2023-11, Vol.142, p.864-864
• Main Authors: Tahira, Yuki, Shide, Kotaro, Kameda, Takuro, Kamiunten, Ayako, Akizuki, Keiichi, Karasawa, Masayoshi, Ikeda, Ryoma, Matsumoto, Kengo, Kubuki, Yoko, Shimoda, Kazuya
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2023-181335

Interferon (IFN)-α exhibits antiviral and antiproliferative effects on normal and neoplastic cells. It is an effective treatment option for myeloproliferative neoplasms (MPNs). The intracellular signaling of IFN-α is triggered by binding of IFN-α to its specific receptors on the cell surface, followed by the activation of tyrosine kinase-2 (TYK2) and Janus kinase-1 (JAK1), both of which are receptor-associated Janus kinases (JAKs). Activated JAKs activate many signaling molecules, including signal transducers and activators of transcription (STATs). Antiviral activity of IFN-α was abrogated in Stat1 deficient-embryonic fibroblasts, however, Tyk2 deficient-cells were resistant to viral infection in the presence of IFN-α, indicating the essential role of STAT1 for the antiviral activity of IFN-α, and TYK2 is not required for that. The antiproliferative effect is another major activity of IFN-α, however, the precise antiproliferative mechanism of IFN-α is not completely understood. We assessed the effect of ropeginterferon-α-2b, a monopegylated IFN-α-2b, on MPN model mice ( Jak2V617F mice), and investigated the role of TYK2 in the antiproliferative effect of IFN-α. Jak2VF mice exhibited leukocytosis and thrombocytosis, and TYK2 deficiency had no effect on MPN phenotypes induced by Jak2VF. IFN-α treatment was associated with a significant reduction in leukocyte and platelet counts in Jak2V617F mice. In contrast, leukocyte and platelet counts remained unchanged after IFN-α treatment in Jak2V617F and Tyk2-/- mice. The proportions of BM progenitor cells as MEP and megakaryocyte lineage cells as MKP were markedly decreased by IFN-α treatment in Jak2V617F mice, whereas IFN-α had no effect on their proportions in Jak2V617F;T yk2-/- mice. Next, we assessed the effects of IFN-a on cytokine-dependent colony formation. The colony numbers of CFU-GM and CFU-Meg from Jak2V617F mice decreased by about half in the presence of IFN-a. In contrast, cytokine-dependent colony formation was not affected by the presence of IFN-a in Jak2V617F; Tyk2-/- mice. GSEA revealed significant enrichment of genes regulating antiproliferation in IFN-α-treated Jak2VF GMPs, but not in IFN-α-treated GMPs from Jak2V617F; Tyk2-/- mice. Collectively, these results indicate that TYK2 plays an essential role in the antiproliferative effect of IFN-α on Jak2VF progenitors. IFN-α was reported to induce HSCs to enter the cell cycle. The significant reduction in quiescent cells and increase in cycling LT-HS