TARGETED POSITRON EMISSION TOMOGRAPHY IMAGING OF CXCR4 EXPRESSION IN PATIENTS WITH ACUTE MYELOID LEUKEMIA
Herhaus P, Habringer S, Philipp-Abbrederis K, Vag T, Gerngross C, Schottelius M, Slotta-Huspenina J, Steiger K, Altmann T, Weißer T, Steidle S, Schick M, Jacobs L, Slawska J, Müller-Thomas C, Verbeek M, Subklewe M, Peschel C, Wester HJ, Schwaiger M, Götze K, Keller U. (12-05-2016).Haematologica, 2016, 10.3324/haematol.2016.142976
Research Area Z
Acute myeloid leukemia originates from leukemia-initiating cells that reside in the protective bone marrow niche. CXCR4/CXCL12 interaction is crucially involved in recruitment and retention of leukemia-initiating cells within this niche. Various drugs targeting this pathway have entered clinical trials. To evaluate CXCR4 imaging in acute myeloid leukemia, we first tested CXCR4 expression in patient-derived primary blasts. Flow cytometry revealed that high blast counts in patients with acute myeloid leukemia correlate with high CXCR4 expression. The wide range of CXCR4 surface expression in patients was reflected in cell lines of acute myeloid leukemia. Next, we evaluated the CXCR4-specific peptide Pentixafor by positron emission tomography imaging in mice harboring CXCR4 positive and CXCR4 negative leukemia xenografts, and in 10 patients with active disease. [(68)Ga]Pentixafor-positron emission tomography showed specific measurable disease in murine CXCR4 positive xenografts, but not when CXCR4 was knocked out with CRISPR/Cas9 gene editing. Five of 10 patients showed tracer uptake correlating well with leukemia infiltration assessed by magnetic resonance imaging. The mean maximal standard uptake value was significantly higher in visually CXCR4 positive patients compared to CXCR4 negative patients. In summary, in vivo molecular CXCR4 imaging by means of positron emission tomography is feasible in acute myeloid leukemia. These data provide a framework for future diagnostic and theranostic approaches targeting the CXCR4/CXCL12-defined leukemia-initiating cell niche.