In Vivo Imaging In the Individualized Mouse Model of Acute Lymphoblastic Leukemia Enables Highly Sensitive and Continuous Follow up of Patient-Derived Xenografts

Abstract 3259

In the individualized xenograft mouse model, acute leukemia cells from patients are transplanted into severely immuno-deficient mice to serve as a preclinical animal model. The use of this mouse model for pre-clinical therapy trials is hampered by the low sensitivity of existing readouts disabling the reliable follow up of single animals. Both secretion of leukemic cells into the blood flow as well as clinical signs, if at all, occur at late states of the disease; readouts in further organs by, e.g., immunohistochemistry or flow cytometry analysis, require organ extraction and can thus be performed only once per mouse.

To overcome this obstacle, we established in vivo imaging in the xenograft mouse model of acute lymphoblastic leukemia (ALL). We engrafted pediatric acute leukemia cells from patients at diagnostic bone marrow aspiration of either diagnosis or relapse. In agreement with published data, mice developed leukemia within weeks to months. Engraftment was followed by easy passaging of cells into further generations of mice. We established lentiviral transduction of xenograft cells which enabled expression of transgenes in these cells. Using lentiviral transduction, we stained patient-derived xenograft ALL-cells using luciferase as a reporter. Transgenic xenograft leukemia cells were visualized once per week by bioluminescence in vivo imaging using a charge-coupled device camera.

Our first data show that in vivo imaging enabled the reliable and continuous follow up of single animals over time. The sensitivity of in vivo imaging in measuring leukemic engraftment was significantly higher compared to current readouts like examination of blood cells. In vivo imaging data support that the leukemic pattern of metastases of patient-derived xenograft ALL-cells in mice highly resembles the distribution of the disease in men. Upon intravenous injection, cells first home to the liver, where they stay alive only for a few weeks. Long-term engraftment is seen in the bone marrow of many different bones and constantly increases over time. Engraftment in spleen indicates rather late stages of disease. This kinetic of engraftment remained constant between several transgenic xenograft samples and between different mice engrafted with the same sample.

Taken together, we have established molecular modulation of xenograft cells which enables expression of luciferase and in vivo bioluminescence imaging as a new sensitive and continuous in vivo readout in mice. In vivo imaging will allow realizing precise preclinical trials in the individualized mouse model in the future.