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

Transcriptional profiling of human acute myeloid leukemia cells lines HEL and SET2 transduced with an IGF1R shRNA and miR-125a sponge. 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 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/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 in mice carrying the JAK2-V617F mutation, which demonstrates 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 unveil novel therapeutic targets for these frequent hematological neoplasias. Human HEL and SET2 cell lines were transduced with IGF1R shRNA and miR-125a sponge, RNA was extracted and transcriptional profiling was obtained with GeneChip Human Gene 2.0 ST Arrays.