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

Abstract

AIRAPL (arsenite-inducible regulatory particle-associated protein-like) is an evolutionarily conserved regulator of cellular proteostasis linked to longevity in nematodes, but whose biological function in mammals is unknown1-3. We show herein that AIRAPL-deficient mice develop a fully-penetrant myeloproliferative neoplastic process4-6. Proteomic analysis of AIRAPL-deficient mice revealed that this protein exerts its antineoplastic function through the regulation of the insulin/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 associated with AIRAPL deficiency, demonstrating its causal involvement in the pathogenesis of myeloproliferative neoplasms. Consistent with its proposed role as a tumor suppressor of myeloid transformation, we have found a widespread down-regulation of AIRAPL in human myeloproliferative disorders, through a silencing mechanism mediated by miR-125a-3p. Collectively, these findings support the oncogenic relevance of proteostasis deregulation in hematopoietic cells, and unveil novel therapeutic targets for these frequent hematological neoplasias