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

Program: Oral and Poster Abstracts
Type: Oral
Session: 631. Myeloproliferative Syndromes and Chronic Myeloid Leukemia: Basic and Translational: Lineage Tracing and Novel Target Discovery
Hematology Disease Topics & Pathways:
Research, Fundamental Science
Monday, December 11, 2023: 4:00 PM

Yuki Tahira1*, Kotaro Shide, MD, PhD2, Takuro Kameda, MD3, Ayako Kamiunten3*, Keiichi Akizuki, MD4*, Masayoshi Karasawa5*, Ryoma Ikeda5*, Kengo Matsumoto5*, Yoko Kubuki, MD, PhD5* and Kazuya Shimoda, MD, PhD3

1Hematol., University of Miyazaki, Miyazaki, Japan, Miyazaki City, Japan
2Faculty of Medicine, Miyazaki Univ., Miyazaki, JPN
3University of Miyazaki, Miyazaki, Japan
4Division of Hematology, Diabetes, and Endocrinology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
5Division of Hematology, Diabetes, and Endcrinology University of Miyazaki, Miyazaki, JPN

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;Tyk2-/- 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-HSCs in Jak2VF compared to WT HSCs after IFN-α treatment was reported (Mullally et al. Blood 2013). Consistent with previous reports, the proportion of long-term HSCs in BM from Jak2VF mice was decreased by 8-weeks-IFN-α treatment, however, this IFN-α effect was not observed when TYK2 was absent. In the pool of phenotypic long-term HSCs, there are subsets of stem cells with an intrinsic megakaryocytic bias and a propensity to commit directly to the megakaryocytic lineage. In the JAK2VF mutant fraction of HSCs from recipient mice transplanted with JAK2VF and WT BM cells, IFN-α treated mice were reported to show an increase in the percentage of CD41high, megakaryocyte-skewed HSCs (Rao et al. Blood 2021). Consistent with this report, IFN-α treatment increased the proportion of CD41highHSCs and decreased that of CD41lowHSCs in BM from Jak2VF mice, and again, IFN-α-induced megakaryocytic bias of HSCs was not observed in TYK2 deficient HSCs. IFN-α had similar effect on Jak2VF-HSCs in recipient mice transplanted with Jak2VF and WT BM cells, and this IFN-α effect was not observed when TYK2 was absent. These observations indicate that TYK2 is essential for the effects of IFN-α on HSCs.

These results indicate that TYK2 is indispensable for the effects of IFN-α on improvement of MPN features.

Disclosures: Tahira: PharmaEssentia: Research Funding.

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