Journal
NATURE MEDICINE
Volume 22, Issue 1, Pages 91-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4013
Keywords
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Funding
- Ministerio de Economia y Competitividad
- Instituto de Salud Carlos III (RTICC)
- Principado de Asturias, Spain
- Fundacion Bancaria Caja de Ahorros de Asturias
- Banco Santander through its Santander Universities Global Division
- Bloodwise [13003]
- Wellcome Trust [104710/Z/14/Z]
- Medical Research Council
- Kay Kendall Leukaemia Fund
- Cambridge National Institute for Health Research Biomedical Research Center
- Cambridge Experimental Cancer Medicine Centre
- Leukemia and Lymphoma Society of America [07037]
- Wellcome Trust
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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(1-3). 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(4-6). 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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