miR-21 is required for hematopoietic cell viability following radiation exposure

Abstract Radiation therapy is an essential intervention used in the treatment plan of more than half of cancer patients. With the increasing use of hypofractionated radiation regimens, concurrent use of radiation and chemotherapy, targeted agents and immunotherapy, the risk of radiation-induced toxicities is increased. Hematopoietic toxicity caused by radiation limits a patient’s options for subsequent systemic therapy. However, much remains unknown about the molecular underpinnings responsible for radiation-induced hematopoietic toxicity. MicroRNA (miRNA) are small, non-coding RNA involved in post-transcriptional regulation of gene expression and are associated with essential cellular processes. miR-21 is a potent oncomiR that is dysregulated in a significant fraction of human malignancies, and its overexpression is linked to poor overall survival, chemoresistance, and radioresistance in several human cancers. However, the contribution of miR-21 in governing radiation sensitivity in normal, untransformed cells, and the impact of silencing this miRNA in normal tissues remains largely unexplored. We determined ionizing radiation significantly increased miR-21 levels in radio-sensitive tissues, but not in radio- insensitive tissues, suggesting it may have a critical function in the normal tissue response to radiation. To test this concept, we generated miR-21 knockout mice. Mice lacking one or both alleles of miR-21 showed reduced numbers of hematopoietic stem and progenitor cells (HSPCs) and increased sensitivity to an LD50/30 dose of total body irradiation (TBI) with evidence of bone marrow failure compared to wild-type mice. Transplantation of wild-type bone marrow into irradiated miR-21 -deficient mice rescued the mice from death. Thus, our data identify miR-21 as a critical component of HSPC viability and essential for bone marrow recovery following irradiation. Further investigation is warranted to determine if miR-21 can be used to stratify patients at risk for hematopoietic toxicity following irradiation.