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Interferon-alpha and the pathogenesis of myeloproliferative disorders

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Abstract

Interferon-alpha (IFN-α), a molecule with multiple biological actions, is widely used in the treatment of chronic myelogenous leukemia (CML) and the other myeloproliferative disorders. This glycoprotein belonging to the type I subfamily of interferons has been recombinantly manufactured and has been approved for the biotherapy of CML, now becoming the first line of treatment for CML patients in chronic phase who are not candidates for allogeneic hematopoietic stem cell or bone marrow transplantation. Interferon-alpha action involves binding to its cell membrane receptor and initiation of an intracellular signal transduction cascade. Two major pathways mediate the biologic actions of IFN-α. The JAK-STAT pathway leads to phosphorylation and activation of STAT1 and STAT2 molecules and transcription of genes like p21 and caspase-1 resulting in cycle arrest and apoptosis. The PKR (protein kinase ds RNA-induced) kinase phosphorylates and inhibits the eukaryotic initiator of translation eIF-2α leading again to apoptosis. The PKR kinase cascade also leads to activation of the transcription factor NF-κB. The relevance of this activation is unclear and it is possible that NF-κB has not had the opportunity to transcribe its target genes as it is a substrate of effector caspases and is maybe cleaved by them before exerting any transcription activity. Through the JAK-STAT and the PKR kinase pathways IFN-α is able to modify the proliferative and antiapoptotic actions of the constitutively activated kinase bcr-abl, the product of the t(9;22) translocation present in CML, and has therapeutic effects in this disease.

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  1. Divisions of Hematology and Medical Oncology, Department of Medicine, Mount Sinai Hospital and Mount Sinai School of Medicine, One G Levy Place, 10029, New York, NY, USA

    IA Voutsadakis

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Voutsadakis, I. Interferon-alpha and the pathogenesis of myeloproliferative disorders. Med Oncol 17, 249–257 (2000). https://doi.org/10.1007/BF02782189

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