Deregulation of IGF1R Proteostasis Promotes Myeloid Transformation

Arsenite-inducible RNA-associated protein-like (AIRAPL; encoded by ZFAND2B) is an evolutionarily conserved endoplasmic reticulum protein known to regulate cellular proteostasis in Caenorhabditis elegans, but its function in mammals is unknown. Osorio and colleagues generated a Zfand2b^−/− mouse, which has a number of defects including a shortened lifespan, progressive weight loss, splenomegaly due to extramedullary hematopoiesis and myeloid lineage expansion, elevated peripheral blood leukocytes, and increased myeloid cells that collectively recapitulate myeloproliferative neoplasms (MPN). Zfand2b^−/− mice had increased expression and phosphorylation of IGF1R, and in vitro overexpression of AIRAPL led to a reduction in IGF1R levels that was reversible by proteasome inhibition, suggesting a mechanism of AIRAPL-mediated IGF1R regulation involving ubiquitination and degradation by the proteasome. Consistent with these findings, AIRAPL expression increased IGF1R monoubiquitination, and AIRAPL immunoprecipitated with proteasome and ER-associated degradation subunits. AIRAPL associated only with pro-IGF1R, and reduced the levels of mature IGF1R translocated out of the ER, indicating that AIRAPL modulates IGF1R levels by regulating the translocation and degradation of IGF1R. Igf1r haploinsufficiency or inhibition in Zfand2b^−/− mice resulted in a reduction in the MPN phenotypes, supporting a role for IGF1R as a driver of MPN in Zfand2b^−/− mice. The mouse data were validated in human MPNs, which did not express AIRAPL and exhibited increased IGF1R expression. Increased IGF1R expression associated with AIRAPL loss was similarly observed in a MPN mouse model (Jak2^V617F), and in acute myeloid leukemia cell lines with the JAK2^V617 mutation, IGF1R inhibition induced growth arrest, whereas overexpression increased proliferation. Mechanistically, ZFAND2B expression was found to be regulated in MPNs by the miRNA miR-125a-3p, and the reduction of this miRNA resulted in a reversion of the myeloproliferative phenotype. Altogether, these findings indicate that AIRAPL acts as a tumor suppressor in myeloid cells by negatively regulating IGF1R and provide a rationale for evaluation of IGF1R inhibitors in patients with MPNs.

Osorio FG, Soria-Valles C, Santiago-Fernández O, Bernal T, Mittelbrunn M, Colado E, et al. Loss of the proteostasis factor AIRAPL causes myeloid transformation by deregulating IGF-1 signaling. Nat Med 2016;22:91–6.

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