Essential Role for the Mnk Pathway in the Inhibitory Effects of Type I Interferons on Myeloproliferative Neoplasm (MPN) Precursors

• Published in: The Journal of biological chemistry 2013-08, Vol.288 (33), p.23814-23822
• Main Authors: Mehrotra, Swarna, Sharma, Bhumika, Joshi, Sonali, Kroczynska, Barbara, Majchrzak, Beata, Stein, Brady L., McMahon, Brandon, Altman, Jessica K., Licht, Jonathan D., Baker, Darren P., Eklund, Elizabeth A., Wickrema, Amittha, Verma, Amit, Fish, Eleanor N., Platanias, Leonidas C.
• Format: Article
• Language: English
• Subjects: Animals; Antiviral Agents; Bone Marrow Neoplasms - metabolism; Bone Marrow Neoplasms - pathology; Cell Differentiation; Cell Line, Transformed; Erythroid Cells - drug effects; Erythroid Cells - metabolism; Erythroid Cells - pathology; Eukaryotic Initiation Factor-4E - metabolism; Humans; Innate Immunity; Interferon; Interferon-alpha - pharmacology; Interferon-beta - pharmacology; Intracellular Signaling Peptides and Proteins - metabolism; Janus Kinases - genetics; Janus Kinases - metabolism; MAP Kinases (MAPKs); Mice; Mutation - genetics; Myeloproliferative Disorders - metabolism; Myeloproliferative Disorders - pathology; Phosphatidylinositol 3-Kinase; Protein-Serine-Threonine Kinases - metabolism; RNA; Signal Transduction; Signal Transduction - drug effects; Translation Control; Translation Initiation Factors
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.476192

The mechanisms of generation of the antineoplastic effects of interferons (IFNs) in malignant hematopoietic cells remain to be precisely defined. We examined the activation of type I IFN-dependent signaling pathways in malignant cells transformed by Jak2V617F, a critical pathogenic mutation in myeloproliferative neoplasms (MPNs). Our studies demonstrate that during engagement of the type I IFN receptor (IFNAR), there is activation of Jak-Stat pathways and also engagement of Mnk kinases. Activation of Mnk kinases is regulated by the Mek/Erk pathway and is required for the generation of IFN-induced growth inhibitory responses, but Mnk kinase activation does not modulate IFN-regulated Jak-Stat signals. We demonstrate that for type I IFNs to exert suppressive effects in malignant hematopoietic progenitors from patients with polycythemia vera, induction of Mnk kinase activity is required, as evidenced by studies involving pharmacological inhibition of Mnk or siRNA-mediated Mnk knockdown. Altogether, these findings provide evidence for key and essential roles of the Mnk kinase pathway in the generation of the antineoplastic effects of type I IFNs in Jak2V617F-dependent MPNs. Background: The mechanisms by which IFNs generate antineoplastic responses remain to be defined. Results: Type I IFN treatment results in activation of the Mnk/eIF4E pathway in Jak2V617F-transformed cells, and this activation is required for the antineoplastic effect. Conclusion: Mnk kinases are essential for the antineoplastic effects of IFN. Significance: This study provides evidence for a key mechanism mediating the effects of IFNs in malignant MPN precursors.