Exosomal miR-26a delivery increases erythroid expansion in models of Diamond-Blackfan anemia

Diamond-Blackfan anemia (DBA) is a pure red blood cell aplasia with a predisposition toward cancer. In DBA erythroid progenitors, nemo-like kinase (NLK) is activated, and mammalian target of rapamycin complex 1 (mTORC1) activity is suppressed. Systemic leucine administration high enough to hyperstimulate mTORC1 improves erythroid expansion in patients and animal models of DBA. However, leucine at such high doses significantly increases malignant transformation of nonerythroid cells upon exposure to carcinogens, heightening cancer risk in these patients. Here we show that exosomal delivery of miR-26a restores basal mTORC1 activity in erythroid progenitors by targeting the NLK transcript for degradation. miR-26a delivery does not hyperstimulate mTORC1, but removal of NLK-mediated mTORC1 suppression primes erythroid cells for mTORC1 hyperstimulation at a 10-fold lower systemic dose of leucine. Delivery of exosomal miR-26a supports optimal mTORC1 hyperstimulation and erythroid expansion with the administration of a leucine dose that does not increase the risk of transformation in nonerythroid cells, thus offering a safe, novel, and effective treatment strategy for increasing erythropoiesis in DBA.