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

The authors uncover a role for the proteostasis modulator AIRAPL as a tumor suppressor in myeloproliferative malignancies, through its regulation of IGFR stability. The results ascribe a biological function to AIRAPL, and they implicate prosteostatic deregulation as an oncogenic mechanism in myeloid transformation, thus suggesting potential novel therapeutic strategies. 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 , 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 Jak2 V617F mutation, thereby demonstrating the causal involvement of this pathway in the pathogenesis of myeloproliferative neoplasms 4 , 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.