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

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. 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.

[1]  N. Young,et al.  Current concepts in the pathophysiology and treatment of aplastic anemia. , 2013, Hematology. American Society of Hematology. Education Program.

[2]  L. Platanias,et al.  The evolution of the TOR pathway and its role in cancer , 2013, Oncogene.

[3]  P. Iversen,et al.  Inhibition of Mnk kinase activity by cercosporamide and suppressive effects on acute myeloid leukemia precursors. , 2013, Blood.

[4]  M. Shinohara,et al.  The role of interferon‐β in the treatment of multiple sclerosis and experimental autoimmune encephalomyelitis – in the perspective of inflammasomes , 2013, Immunology.

[5]  R. Tiu,et al.  Biological rationale and clinical use of interferon in the classical BCR-ABL-negative myeloproliferative neoplasms. , 2013, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[6]  C. Scagnolari,et al.  Antiviral activity of the interferon α family: biological and pharmacological aspects of the treatment of chronic hepatitis C , 2013, Expert opinion on biological therapy.

[7]  L. Rönnblom,et al.  The interferon signature in autoimmune diseases , 2013, Current opinion in rheumatology.

[8]  L. Rönnblom,et al.  Type I interferons in Sjögren's syndrome. , 2013, Autoimmunity reviews.

[9]  D. Karussis.  Immunotherapy of Multiple Sclerosis , 2013, BioDrugs.

[10]  M. Diamond,et al.  The broad-spectrum antiviral functions of IFIT and IFITM proteins , 2012, Nature Reviews Immunology.

[11]  J. Licht,et al.  Sprouty Proteins Are Negative Regulators of Interferon (IFN) Signaling and IFN-inducible Biological Responses* , 2012, The Journal of Biological Chemistry.

[12]  J. Kirkwood,et al.  IFN-α in the Treatment of Melanoma , 2012, The Journal of Immunology.

[13]  T. Barbui,et al.  Experience with pegylated interferon α-2a in advanced myeloproliferative neoplasms in an international cohort of 118 patients , 2012, Haematologica.

[14]  K. Elkon,et al.  Type I IFN system in the development and manifestations of SLE , 2012, Current opinion in rheumatology.

[15]  J. Drenth,et al.  Interferon-α for Patients with Chronic Hepatitis Delta: A Systematic Review of Randomized Clinical Trials , 2012, Antiviral therapy.

[16]  L. Platanias,et al.  Regulatory Effects of Programmed Cell Death 4 (PDCD4) Protein in Interferon (IFN)-Stimulated Gene Expression and Generation of Type I IFN Responses , 2012, Molecular and Cellular Biology.

[17]  B. Su,et al.  Regulatory effects of mTORC2 complexes in type I IFN signaling and in the generation of IFN responses , 2012, Proceedings of the National Academy of Sciences.

[18]  J. Darnell,et al.  The JAK-STAT pathway at twenty. , 2012, Immunity.

[19]  R. Plenge,et al.  JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. , 2012, Immunity.

[20]  C. Proud,et al.  Targeting Mnks for Cancer Therapy , 2012, Oncotarget.

[21]  R. Silver,et al.  Recombinant interferon-α may retard progression of early primary myelofibrosis: a preliminary report. , 2011, Blood.

[22]  R. Hoffman,et al.  The renaissance of interferon therapy for the treatment of myeloid malignancies. , 2011, Blood.

[23]  N. Sonenberg,et al.  Therapeutic inhibition of MAP kinase interacting kinase blocks eukaryotic initiation factor 4E phosphorylation and suppresses outgrowth of experimental lung metastases. , 2011, Cancer research.

[24]  Ayalew Tefferi,et al.  Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[25]  Dong-er Zhang,et al.  Interferon-stimulated gene 15 and the protein ISGylation system. , 2011, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[26]  A. Verma,et al.  Essential Role for Mnk Kinases in Type II Interferon (IFNγ) Signaling and Its Suppressive Effects on Normal Hematopoiesis* , 2010, The Journal of Biological Chemistry.

[27]  L. Platanias,et al.  Mechanisms of mRNA translation of interferon stimulated genes. , 2010, Cytokine.

[28]  D. Gilliland,et al.  Transcriptional Profiling of Polycythemia Vera Identifies Gene Expression Patterns Both Dependent and Independent from the Action of JAK2V617F , 2010, Clinical Cancer Research.

[29]  R. Hoffman,et al.  Interferon-alpha targets JAK2V617F-positive hematopoietic progenitor cells and acts through the p38 MAPK pathway. , 2010, Experimental hematology.

[30]  S. Indraccolo.  Interferon-α as angiogenesis inhibitor: Learning from tumor models , 2010, Autoimmunity.

[31]  A. Redig,et al.  Type I interferon (IFN)-dependent activation of Mnk1 and its role in the generation of growth inhibitory responses , 2009, Proceedings of the National Academy of Sciences.

[32]  L. Platanias,et al.  Role of Schlafen 2 (SLFN2) in the Generation of Interferon α-induced Growth Inhibitory Responses* , 2009, The Journal of Biological Chemistry.

[33]  J. Rey,et al.  PEG‐IFN‐α‐2a therapy in patients with myelofibrosis , 2009 .

[34]  L. Platanias,et al.  Interferon-Dependent Engagement of Eukaryotic Initiation Factor 4B via S6 Kinase (S6K)- and Ribosomal Protein S6K-Mediated Signals , 2009, Molecular and Cellular Biology.

[35]  A. Redig,et al.  Activation of Protein Kinase Cη by Type I Interferons* , 2009, Journal of Biological Chemistry.

[36]  R. Chung,et al.  Treatment failure in hepatitis C: mechanisms of non-response. , 2009, Journal of hepatology.

[37]  S. Chevret,et al.  Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. , 2008, Blood.

[38]  C. Proud,et al.  The Mnks: MAP kinase-interacting kinases (MAP kinase signal-integrating kinases). , 2008, Frontiers in bioscience : a journal and virtual library.

[39]  L. Platanias,et al.  Role of the Akt pathway in mRNA translation of interferon-stimulated genes , 2008, Proceedings of the National Academy of Sciences.

[40]  Tahlia L. Weis,et al.  Osteopontin Regulates Actin Cytoskeleton and Contributes to Cell Proliferation in Primary Erythroblasts* , 2008, Journal of Biological Chemistry.

[41]  C. Proud,et al.  The PSF·p54nrb Complex Is a Novel Mnk Substrate That Binds the mRNA for Tumor Necrosis Factor α* , 2008, Journal of Biological Chemistry.

[42]  Graham R. Foster,et al.  Interferons at age 50: past, current and future impact on biomedicine , 2007, Nature Reviews Drug Discovery.

[43]  A. Redig,et al.  The protein kinase C (PKC) family of proteins in cytokine signaling in hematopoiesis. , 2007, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[44]  S. Pestka.  The Interferons: 50 Years after Their Discovery, There Is Much More to Learn* , 2007, Journal of Biological Chemistry.

[45]  N. Sonenberg,et al.  Regulatory Effects of Mammalian Target of Rapamycin-activated Pathways in Type I and II Interferon Signaling* , 2007, Journal of Biological Chemistry.

[46]  O. Linder,et al.  A phase II trial of pegylated interferon alpha-2b therapy for polycythemia vera and essential thrombocythemia: feasibility, clinical and biologic effects, and impact on quality of life. , 2006, Cancer.

[47]  L. Platanias,et al.  The p38 mitogen-activated protein kinase pathway in interferon signal transduction. , 2005, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[48]  Rodolfo Marquez,et al.  The Mnks are novel components in the control of TNF alpha biosynthesis and phosphorylate and regulate hnRNP A1. , 2005, Immunity.

[49]  L. Platanias.  Mechanisms of type-I- and type-II-interferon-mediated signalling , 2005, Nature Reviews Immunology.

[50]  Sandra A. Moore,et al.  Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. , 2005, Cancer cell.

[51]  L. Platanias.  Map kinase signaling pathways and hematologic malignancies. , 2003, Blood.

[52]  A. Verma,et al.  Signaling Via the Interferon-α Receptor in Chronic Myelogenous Leukemia Cells , 2002 .

[53]  Amit Verma,et al.  The p38 MAPK Pathway Mediates the Growth Inhibitory Effects of Interferon-α in BCR-ABL-expressing Cells* , 2001, The Journal of Biological Chemistry.

[54]  L. Platanias,et al.  Signaling pathways activated by interferons. , 1999, Experimental hematology.

[55]  G. Stark,et al.  How cells respond to interferons. , 1998, Annual review of biochemistry.

[56]  C. Peschel,et al.  Influence of interferon-alpha on cytokine expression by the bone marrow microenvironment--impact on treatment of myeloproliferative disorders. , 1996, Leukemia & lymphoma.

[57]  S. Baron,et al.  The interferons. Mechanisms of action and clinical applications. , 1991, JAMA.

[58]  R. Silver.  RECOMBINANT INTERFERON-ALPHA FOR TREATMENT OF POLYCYTHAEMIA VERA , 1988, The Lancet.

[59]  B. Dallapiccola,et al.  Letter: X long-arm deletion with features of Turner's syndrome. , 1974, Lancet.

[60]  L. Platanias,et al.  Mnk kinases in cytokine signaling and regulation of cytokine responses , 2015, Biomolecular concepts.

[61]  S. Verstovsek,et al.  Novel tumor antigens elicit anti-tumor humoral immune reactions in a subset of patients with polycythemia vera. , 2007, Clinical immunology.

[62]  M. Griesshammer,et al.  Pegylated interferon for the treatment of high risk essential thrombocythemia: results of a phase II study. , 2005, Haematologica.

[63]  Z. Estrov,et al.  Pilot study of pegylated interferon-alpha 2b in patients with essential thrombocythemia , 2002, Cancer Chemotherapy and Pharmacology.

[64]  L. Platanias,et al.  Activation of the p 38 Mitogen-activated Protein Kinase by Type I Interferons , 1999 .

[65]  K C Zoon,et al.  Interferons and their actions. , 1987, Annual review of biochemistry.