Abstract
PurposeAblative bone marrow irradiation is an integral part of hematopoietic stem cell transplantation. These treatment regimens are based on classically held models of radiation dose and the bone marrow response. Flt-3 ligand (FL) has been suggested as a marker of hematopoiesis and bone marrow status but the kinetics of its response to bone marrow irradiation has yet to be fully characterized. In the current study, we examine plasma FL response to total body and partial body irradiation in mice and its relationship with irradiation dose, time of collection and pattern of bone marrow exposure.Materials/MethodsC57BL6 mice received a single whole body or partial body irradiation dose of 1–8 Gy. Plasma was collected by mandibular or cardiac puncture at 24, 48 and 72 hr post-irradiation as well as 1–3 weeks post-irradiation. FL levels were determined via ELISA assay and used to generate two models: a linear regression model and a gated values model correlating plasma FL levels with radiation dose.ResultsAt all doses between 1–8 Gy, plasma FL levels were greater than control and the level of FL increased proportionally to the total body irradiation dose. Differences in FL levels were statistically significant at each dose and at all time points. Partial body irradiation of the trunk areas, encompassing the bulk of the hematopoietically active bone marrow, resulted in significantly increased FL levels over control but irradiation of only the head or extremities did not. FL levels were used to generate a dose prediction model for total body irradiation. In a blinded study, the model differentiated mice into dose received cohorts of 1, 4 or 8 Gy based on plasma FL levels at 24 or 72 hrs post-irradiation.ConclusionOur findings indicate that plasma FL levels might be used as a marker of hematopoietically active bone marrow and radiation exposure in mice.
Highlights
Total body irradiation (TBI) used in conjunction with myeloablative chemotherapy remains the clinical standard for many conditioning regimens for bone marrow transplantation
At all doses between 1–8 Gy, plasma Flt-3 ligand (FL) levels were greater than control and the level of FL increased proportionally to the total body irradiation dose
Our findings indicate that plasma FL levels might be used as a marker of hematopoietically active bone marrow and radiation exposure in mice
Summary
Total body irradiation (TBI) used in conjunction with myeloablative chemotherapy remains the clinical standard for many conditioning regimens for bone marrow transplantation. TBI conditioning regimens were based on classical models of bone marrow sensitivity to radiation conducted in animals, and recent TBI dosing regimens are the subject of randomized clinical trials as new TBI therapies are tailored to modern HSCT and to reduce regimen-related toxicity. [6,7,8] In patients undergoing fractionated radiotherapy, a direct correlation has been made between plasma FL levels and the percentage of irradiated bone marrow. [9] An increase in plasma FL levels has been correlated with a decrease in WBC count in patients undergoing stem cell transplantation. FL is primarily expressed in the bone marrow though FL mRNA is found in a wide variety of tissues. [6,7,8] In patients undergoing fractionated radiotherapy, a direct correlation has been made between plasma FL levels and the percentage of irradiated bone marrow. [9] An increase in plasma FL levels has been correlated with a decrease in WBC count in patients undergoing stem cell transplantation. [10] In several recent case reports where individuals were accidently exposed to radiation, FL was used to monitor hematopoietic aplasia and FL levels appeared to correlate with the amount of radiation exposure. [11,12,13]
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