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

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 unknown1,2,3. 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 Jak2V617F mutation, thereby demonstrating the causal involvement of this pathway in the pathogenesis of myeloproliferative neoplasms4,5,6. 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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Figure 1: MPNs in Zfand2b-deficient mice.
Figure 2: AIRAPL regulates IGF1R steady-state levels.
Figure 3: IGF1R inhibition prevents myeloproliferative neoplasms.
Figure 4: AIRAPL and IGF1R alterations in JAK2-driven MPN.

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Acknowledgements

We thank A.A. Ferrando, D.A. Puente, A.R. Folgueras, G.R. Ordoñez, I. Martín-Subero, A. Gutiérrez-Fernández, G. Mariño and E. Luño for advice. We also thank S. Jeay (Novartis Pharma AG, Basel Area, Switzerland; NVP-AEW541), M. Holzenberger (Faculté de médecine Pierre et Marie Curie, Paris; Igf1r-haploinsuficient mice), M.J. Muñoz Ruiz (Universidad Pablo de Olavide, Sevilla; GM6 C. elegans strain) and F.G. Wulczyn (Universitätsmedizin Berlin, Berlin; miR-125a sponge) for providing reagents. We thank A. Moyano and R. Feijoo for excellent technical assistance, and the Servicio de Histopatología (IUOPA) for histological studies. This work was supported by grants from Ministerio de Economía y Competitividad (C.L.-O.), Instituto de Salud Carlos III (RTICC) (C.L.-O.), and Principado de Asturias, Spain (J.M.P.F). We also thank the generous support by J.I. Cabrera, A.I. Campos and M. Secades. The Instituto Universitario de Oncología is supported by Fundación Bancaria Caja de Ahorros de Asturias. C.L.-O. is an Investigator of the Botin Foundation supported by Banco Santander through its Santander Universities Global Division. Work in the Green laboratory is supported by Bloodwise (grant ref. 13003), the Wellcome Trust (grant ref. 104710/Z/14/Z), the Medical Research Council, the Kay Kendall Leukaemia Fund, the Cambridge National Institute for Health Research Biomedical Research Center, the Cambridge Experimental Cancer Medicine Centre, the Leukemia and Lymphoma Society of America (grant ref. 07037), and a core support grant from the Wellcome Trust and the Medical Research Council to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute.

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F.G.O. performed experimental work, data interpretation and preparation of the manuscript. C.S.-V., O.S.-F., T.B., M.M., E.C., F.R., E.B.-K., J.V., M.P.d.-l.R., J.C. and A.F. performed experimental work. J.L. and A.R.G. provided critical materials and participated in the preparation of the manuscript. J.M.P.F. and C.L.-O. supervised research and project planning, data interpretation and preparation of the manuscript. All authors discussed the results and implications and commented on the manuscript at all stages.

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Correspondence to José M P Freije or Carlos López-Otín.

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Osorio, F., Soria-Valles, C., Santiago-Fernández, O. et al. Loss of the proteostasis factor AIRAPL causes myeloid transformation by deregulating IGF-1 signaling. Nat Med 22, 91–96 (2016). https://doi.org/10.1038/nm.4013

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