2. Academic Validation
  3. Loss of the proteostasis factor AIRAPL causes myeloid transformation by deregulating IGF-1 signaling

Loss of the proteostasis factor AIRAPL causes myeloid transformation by deregulating IGF-1 signaling

  • Nat Med. 2016 Jan;22(1):91-6. doi: 10.1038/nm.4013.
Fernando G Osorio 1,  Clara Soria-Valles 1,  Olaya Santiago-Fernández 1,  Teresa Bernal 1 2,  María Mittelbrunn 1 3 4,  Enrique Colado 2,  Francisco Rodríguez 1,  Elena Bonzon-Kulichenko 5,  Jesús Vázquez 5,  Montserrat Porta-de-la-Riva 6 7,  Julián Cerón 6,  Antonio Fueyo 8,  Juan Li 9 10,  Anthony R Green 9 10 11,  José M P Freije 1,  Carlos López-Otín 1
Affiliations

Affiliations

  • 1 Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain.
  • 2 Servicio de Hematología, Hospital Universitario Central de Asturias, Oviedo, Spain.
  • 3 Instituto de Investigación Sanitaria, Hospital 12 de Octubre (i+12), Madrid, Spain.
  • 4 Departamento de Bioquímica, Facultad de Medicina, Universidad Autónoma de Madrid (UAM), Madrid, Spain.
  • 5 Laboratory of Cardiovascular Proteomics, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
  • 6 Area of Cancer and Human Molecular Genetics, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
  • 7 Caenorhabditis elegans Facility, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
  • 8 Área de Fisiología, Departamento de Biología Funcional, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain.
  • 9 Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK.
  • 10 Department of Haematology, University of Cambridge, Cambridge, UK.
  • 11 Department of Haematology, Addenbrooke's Hospital, Cambridge, UK.
PMID: 26692333 DOI: 10.1038/nm.4013
Abstract

AIRAPL (arsenite-inducible RNA-associated protein-like) is an evolutionarily conserved regulator of cellular proteostasis linked to longevity in nematodes, but its biological function in mammals is unknown. We show herein that AIRAPL-deficient mice develop a fully-penetrant myeloproliferative neoplastic process. Proteomic analysis of AIRAPL-deficient mice revealed that this protein exerts its antineoplastic function through the regulation of the Insulin/insulin-like growth factor 1 (IGF-1) signaling pathway. We demonstrate that AIRAPL interacts with newly synthesized insulin-related growth factor-1 receptor (IGF1R) polypeptides, promoting their ubiquitination and proteasome-mediated degradation. Accordingly, genetic and pharmacological IGF1R inhibitory strategies prevent the hematological disease found in AIRAPL-deficient mice as well as that in mice carrying the JAK2(V617F) mutation, thereby demonstrating the causal involvement of this pathway in the pathogenesis of myeloproliferative neoplasms. Consistent with its proposed role as a tumor suppressor of myeloid transformation, AIRAPL expression is widely abrogated in human myeloproliferative disorders. Collectively, these findings support the oncogenic relevance of proteostasis deregulation in hematopoietic cells, and they unveil novel therapeutic targets for these frequent hematological neoplasias.

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