Abstract
Total body irradiation (TBI) is a common myeloablative preparative regimen used in acute myeloid and lymphoblastic leukemia patients before allogenic hematopoietic stem cell transplantation (HSCT). The inefficient clearance of tumor cells and radiation-induced toxicity to normal tissues is attributed to relapse and morbidity in a significant fraction of patients. Developing biomarkers that indicate an individual's physiological response to radiation will allow personalized treatment and follow-up. We investigated the utility of circulating microRNA150-5p (miR150) for evaluation of radiation dose response. Age-, sex-, and strain-matched wild type and miR150 null (knockout, KO) mice were subjected to TBI and evaluated for the impact of circulating miR150 expression on survival and hematologic endpoints. Dose- and time-dependent changes of the miR150 level in bone marrow were assessed using flow cytometry. The functional roles of miR150 in cellular response to radiation were evaluated using apoptosis assay. miR150 expression in leukemic cell lines and in blood collected from leukemia patients with diverse outcomes was evaluated by quantitative RT-PCR. Absence of miR150 in mice conferred resistance to radiation injury and resulted in accelerated recovery of lymphoid and myeloid cells after ablative or partially ablative TBI in mice. Overexpression of miR150 resulted in a higher percentage of cells at G2/M phases of cell cycle, which is associated with increased sensitivity and susceptibility to apoptotic cell death after radiation. Levels of circulating miR150 were found to be decreased after radiation in leukemia patients and exhibited an inverse correlation with recurrence. The current study demonstrates the utility of an miR150-based blood test for rapid evaluation of the efficiency of marrow ablation and recovery after radiation and HSCT. The internally controlled blood test may provide near real-time evaluation of functional marrow that will allow optimal dosing based on an individual's physiologic response to radiation.
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